Method for tissue regeneration

ABSTRACT

The invention relates to DNA-sequences, their use and the use of DNA-sequences of the MAG gene or genes encoding the high mobility group proteins, agents for the treatment of various diseases including tumors, influencing the development of the vascular system, as well as for contraception and tissue regeneration, and appropriate kits and processes. The sequences, agents, uses, kits and processes enable the specific influencing of molecular mechanisms that jointly form the basis for various diseases, the development of the vascular system, the contraception and the regeneration of tissue. Thus, the disadvantages associated with other agents or processes are decreased.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/024,522, filed Dec. 29, 2004, which is a continuation of U.S.application Ser. No. 09/951,107, filed Sep. 10, 2001, now abandoned,which is a continuation of U.S. application Ser. No. 09/105,542, filedJun. 26, 1998, now U.S. Pat. No. 6,323,329, which is acontinuation-in-part of U.S. application Ser. No. 09/102,321, filed Jun.22, 1998, now abandoned, which is a continuation of InternationalApplication PCT/DE96/02494, filed Dec. 20, 1996, which designates theUnited States and which claims priority to German application DE 195 48122.4, filed Dec. 21, 1995.

FIELD OF THE INVENTION

The present invention relates to the fields of molecular biology andbiotechnology. More specifically, the invention relates to compositionsand methods based on DNA sequences of MAG genes or of genes of the highmobility group proteins and substances for: (1) treatment of diseases;(2) contraception; and (3) tissue generation. Corresponding kits andmethods also are disclosed.

BACKGROUND OF THE INVENTION

When studying the molecular basis of aberrant cell growth thataccompanies the growth of benign and malignant tumors, so-called MAGgenes (multiple-tumor aberration growth genes) were identified asbelonging to the group to which high mobility group protein (HMG genes)genes belong.

The genes of the high mobility group proteins, such as the HMGI-C genelocated on the human chromosome 12 and the HMGI-Y gene on chromosome 6,which, among the known HMG genes, has the relative highest homologousdegree compared to HMGI-C, usually have components that code forDNA-bonding protein parts and components that code for protein-bondingcomponents.

Studies by Schoenmakers et al., (Nature Genet 10:436 (1995)) studiesshow that mutations of the HMGI-C gene are the most likely cause of thedevelopment of many benign human tumors, some groups of which are:uterus leiomyoma, lipoma, pleomorphic adenoma of the salivary gland,endometrium polyps, hamarto chondroma of the lung, aggressiveangiomyxoma, and fibroadenoma of the mamma.

With the exception of the pleomorphic adenoma, all of the above tumorsare of mesenchymal origin or contain mesenchymal components that areconsidered to be monoclonal. Today the pleomorphic adenoma is mostlyconsidered to be an epithelial tumor, although its histogenesis stillhas not been completely determined and there are discussions concerningthe participation of mesenchymalic cells in the development of tumors.Many of the tumors sometimes or even regularly show mesenchymalicmetaplasia. Also striking is the appearance of myxoid cartilage in manyof the tumors, which is characteristic of hamarto chondroma of the lungand the pleomorphic adenoma, for example. Ashar et al., (Cell 82:57(1995)) confirmed the findings of Schoenmakers et al., (Nature Genet10:436 (1995)) for the lipoma group.

DEFINITIONS

As used herein, it is to be understood that “HMGI genes” refers to asubfamily of high mobility group protein genes comprising HMGI-C andHMGI(Y). Furthermore, the respective translation products compriseHMGI-C encoded by the HMGI-C gene, and HMGI and HMGY both encoded by theHMGI(Y) gene.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to an isolated polynucleotidehaving a sequence that includes a first sequence encoding each of exons1, 2 and 3 of an HMGI or MAG gene, and a second sequence from a sourceother than an HMGI or MAG gene, wherein the second sequence is a humanDNA sequence which is a sequence other than a sequence immediatelyupstream of exon 1 of the HMGI or MAG gene in a human genome. Accordingto one embodiment of the invention, the second sequence of the isolatedpolynucleotide encodes a gene product which is encoded by one of SEQ IDNOS:1-19. According to another embodiment of the invention, the isolatedpolynucleotide has the sequence of one of SEQ ID NOS:1-19.

A second aspect of the invention relates to an isolated polypeptidehaving a sequence that includes a first sequence encoded by exons 1, 2and 3 of an HMGI or MAG gene, and a second sequence encoded by apolynucleotide from a source other than an HMGI or MAG gene. The secondpolynucleotide is from a human, but has a sequence other than thesequence located immediately upstream of exon 1 of the HMGI or MAG genein the human genome. According to one embodiment of the invention, theisolated polypeptide has a sequence encoded by one of SEQ ID NOS:1-19.

A third aspect of the invention relates to a method for treating tumorsin a mammal. This method includes the steps of administering to themammal an agent which blocks the activity or effect of a DNA selectedfrom the group consisting of an HMGI gene, a MAG gene and apolynucleotide having a sequence which includes at least a firstsequence encoding each of exons 1, 2 and 3 of an HMGI or MAG gene; and asecond sequence which is from a source other than an HMGI or MAG gene.This second sequence is a human DNA sequence and is a sequence otherthan the sequence immediately upstream of exon 1 of the HMGI or MAG genein the human genome. According to one embodiment the DNA has a sequenceof one of SEQ ID NOS:1-19 or a sequence encoding the same amino acidsencoded by SEQ ID NOS:1-19. Alternatively, agent inhibits the formationof transcripts of the HMGI or MAG genes. According to anotherembodiment, the agent decreases the half-life of the HMGI or MAG genetranscripts. According to yet another embodiment, the agent is selectedfrom the group consisting of anti-sense nucleic acid molecules andribozymes. According to still yet another embodiment, the agent is atranslation product of the DNA molecule. According to a furtherembodiment, the administering step involves incorporating the agent intothe tumor. This administering step can include introducing a vector tothe tumor, where this vector includes the DNA or an RNA transcriptthereof, and then expressing the DNA or RNA transcript to createtranslation products thereof which competitively inhibit binding ofcellular HMGI/MAG gene translation products to the cellular genome.According to a different embodiment, the tumor is one which showsexpression of a gene which is selected from the group consisting of HMGIgenes, HMGI-C genes and HMGI-Y genes. In the alternative, the agent canbe a nucleic acid having a sequence that includes at least one AT hookor at least one AT hook-like structure.

A fourth aspect of the invention relates to a method for diagnosing oftumors which includes the steps of. (1) administering to suspected tumortissue a first polynucleotide which is complementary to a secondpolynucleotide that is selected from the group consisting of HMGI genes,MAG genes and nucleic acid molecules having sequences according to oneof SEQ ID NOS.: 1-19; and (2) detecting significant complex formationbetween the first polynucleotide and the second polynucleotide when atumor is present, but not when a tumor is absent. In this instance, thefirst polynucleotide additionally may include a marker or label.

A fifth aspect of the invention relates to a method for diagnosingtumors which includes the steps of: (1) administering to suspected tumortissue a translation product of a polynucleotide selected from the groupconsisting of HMGI genes, MAG genes and nucleic acid molecules havingsequences according to one of SEQ ID NOS.: 1-19; and then (2) detectingsignificant complex formation between the product and the polynucleotidewhen a tumor is present, but not when a tumor is absent. In a preferredembodiment of this method, the translation product includes a marker orlabel.

A sixth aspect of the invention relates to a method for diagnosing oftumors that involves the steps of: (1) administering to suspected tumortissue an antibody to a translation product of a polynucleotide selectedfrom the group consisting of HMGI genes, MAG genes and nucleic acidmolecules having sequences according to one of SEQ ID NOS.: 1-19; andthen (2) detecting significant complex formation between the antibodiesand the translation products when a tumor is present, but not when atumor is absent. In one embodiment of the invented method the antibodyis selected from the group consisting of polyclonal antibodies,monoclonal antibodies and fragments and derivatives thereof. In adifferent embodiment the antibody includes a marker or label.

A seventh aspect of the invention relates to a method for diagnosis ofendometriosis which involves: (1) administering a first polynucleotideto suspected ectopic endometrial tissue complementary to a secondpolynucleotide which is selected from the group consisting of HMGIgenes, MAG genes and nucleic acid molecules having sequences accordingto one of SEQ ID NOS.: 1-19; and then (2) detecting significant complexformation between the first polynucleotide and the second polynucleotidewhen endometriosis is present, but not when endometriosis is absent.According to one embodiment of the invented method the firstpolynucleotide additionally comprises a marker or label.

An eighth aspect of the invention relates to a method for the diagnosisof endometriosis that includes the steps of: (1) administering tosuspected ectopic endometrial tissue a translation product of apolynucleotide which is selected from the group consisting of HMGIgenes, MAG genes and nucleic acid molecules having sequences accordingto one of SEQ ID NOS.: 1-19; and then (2) detecting significant complexformation between the translation product and the polynucleotide whenendometriosis is present, but not when endometriosis is absent.According to one embodiment of the invented method, the translationproduct includes a marker or label.

A ninth aspect of the invention relates to a method for the diagnosis ofendometriosis that includes the steps of: (1) administering to suspectedectopic endometrial tissue an antibody to a translation product of apolynucleotide selected from the group consisting of HMGI genes, MAGgenes and nucleic acid molecules having sequences according to one ofSEQ ID NOS.: 1-19; and then (2) detecting significant complex formationbetween the antibodies and the translation products when endometriosisis present, but not when endometriosis is absent. The antibody may beselected from the group consisting of polyclonal antibodies, monoclonalantibodies and fragments and derivatives thereof. In a preferredembodiment, the antibody includes a marker or label.

A tenth aspect of the invention relates to a method for contraception ina mammal which includes the steps of: (1) administering to the mammal afirst polynucleotide complementary to a second polynucleotide selectedfrom the group consisting of HMGI genes, MAG genes and nucleic acidmolecules having sequences according to one of SEQ ID NOS.: 1-19; andthen (2) forming a complex between said first polynucleotide and saidsecond polynucleotide, thereby inhibiting fertility.

An eleventh aspect of the invention relates to a method forcontraception in a mammal which includes the steps of: (1) administeringto the mammal a translation product of a polynucleotide selected fromthe group consisting of HMGI genes, MAG genes and nucleic acid moleculeshaving sequences according to one of SEQ ID NOS.: 1-19; and then (2)forming a complex between the translation product and thepolynucleotide, thereby inhibiting fertility.

A twelfth aspect of the invention relates to a method for contraceptionin a mammal which includes the steps of: (1) administering to the mammalan antibody to a translation product of a polynucleotide selected fromthe group consisting of HMGI genes, MAG genes and nucleic acid moleculeshaving sequences according to one of SEQ ID NOS.: 1-19; and then (2)forming a complex between the antibodies and the translation products,thereby inhibiting fertility. In a preferred embodiment, the antibody isselected from the group consisting of polyclonal antibodies, monoclonalantibodies and fragments and derivatives thereof.

A thirteen aspect of the invention relates to a method for regeneratingtissue which includes the step of activating expression in the tissue ofa nucleic acid sequence selected from the group consisting of HMGIgenes, MAG genes, nucleic acid sequences according to SEQ ID Nos. 1-19and their derivatives in a cell. The activating step may involveadministering a phorbol ester. Alternatively, the activating step mayinvolve administering the nucleic acid sequence in a vector. Thisnucleic acid sequence can be under transcriptional control of apromoter, and the promoter may be inducible. If the promoter isinducible then the administering step additionally may involveadministering an agent which induces the promoter. According to anotherembodiment of the invention, tissue regeneration occurs in situ.According to a different embodiment, tissue regeneration is achieved byfirst carrying out the activating step in a cell which is then furtherpropagated. In a preferred embodiment of the invented method the tissueto be regenerated is mesenchymal tissue. In one embodiment of theinvention, the mesenchymal tissue is selected from the group comprisingcartilage tissue, muscle tissue, fatty or adipose tissue, connectivetissue and supporting tissue.

A fourteenth aspect of the invention relates to a method forregenerating tissue which involves administering to the tissue atranslation product of a nucleic acid sequence selected from the groupconsisting of HMGI genes, MAG genes, nucleic acid sequences according toSEQ ID Nos. 1-19 and their derivatives. In one embodiment, thetranslation product is administered via an encapsulation technique tosaid tissue. In a different embodiment the tissue is regenerated byfirst carrying out the administering step to a cell which is thenfurther propagated. According to yet another embodiment of the inventionthe tissue regeneration is performed in situ. The tissue to beregenerated particularly may be mesenchymal tissue. When theregeneration is performed in situ, the mesenchymal tissue can beselected from the group consisting of cartilage tissue, muscle tissue,fatty or adipose tissue, connective tissue and supporting tissue.

A fifteenth aspect of the invention relates to a method for inducingangiogenesis which includes the step of activating expression in venousor capillary tissue of a nucleic acid sequence selected from the groupconsisting of HMGI genes, MAG genes, nucleic acid sequences according toSEQ ID Nos. 1-19 and their derivatives in a cell. In one embodiment, theactivating step involves administering a phorbol ester. In anotherembodiment, the activating step involves administering the nucleic acidsequence in a vector. This nucleic acid sequence can be undertranscriptional control of a promoter. This promoter may be an induciblepromoter and the administering step additionally may involveadministering an agent which induces the promoter. In yet anotherpreferred embodiment of the invented method, angiogenesis occurs insitu. Angiogenesis can be achieved by first carrying out the activatingstep in a cell which is then further propagated. Another aspect of theinvention relates to a method for improving the vascular supply ofmyocardial tissue damaged by myocardial infarction, which methodinvolves inducing angiogenesis by activating expression in venous orcapillary tissue of a nucleic acid sequence selected from the groupconsisting of HMGI genes, MAG genes, nucleic acid sequences according toSEQ ID Nos. 1-19 and their derivatives in a cell.

A sixteenth aspect of the invention relates to a method for inducingangiogenesis, comprising administering to venous or capillary tissue atranslation product of a nucleic acid sequence selected from the groupconsisting of HMGI genes, MAG genes, nucleic acid sequences according toSEQ ID Nos. 1-19 and their derivatives. In a preferred embodiment, thetranslation product is administered via an encapsulation technique tosaid tissue. In another preferred embodiment angiogenesis occurs byfirst carrying out the administering step to a cell which is thenfurther propagated. In still another preferred embodiment, angiogenesisoccurs in situ. A related aspect of the invention relates to a methodfor improving vascular supply of myocardial tissue damaged by myocardialinfarction. This method involves inducing angiogenesis by administeringto venous or capillary tissue a translation product of a nucleic acidsequence selected from the group consisting of HMGI genes, MAG genes,nucleic acid sequences according to SEQ ID Nos. 1-19 and theirderivatives.

A seventeenth aspect of the invention relates to a method for inhibitingangiogenesis in a mammal. This method involves first administering tothe mammal a first polynucleotide complementary to a secondpolynucleotide selected from the group consisting of HMGI genes, MAGgenes and nucleic acid molecules having sequences according to one ofSEQ ID NOS.: 1-19; and then forming a complex between the firstpolynucleotide and the second polynucleotide, thereby inhibitingangiogenesis. A related aspect of the invention regards a method ofpreventing or treating loss of sight as a consequence ofneovascularization by inhibiting angiogenesis according to methodinvolves first administering to the mammal a first polynucleotidecomplementary to a second polynucleotide selected from the groupconsisting of HMGI genes, MAG genes and nucleic acid molecules havingsequences according to one of SEQ ID NOS.: 1-19; and then forming acomplex between the first polynucleotide and the second polynucleotide,thereby inhibiting angiogenesis.

An eighteenth aspect of the invention relates to a method for inhibitingangiogenesis in a mammal which involves the steps of administering tothe mammal a translation product of a polynucleotide selected from thegroup consisting of HMGI genes, MAG genes and nucleic acid moleculeshaving sequences according to one of SEQ ID NOS.: 1-19; and then forminga complex between the translation product and the polynucleotide,thereby inhibiting angiogenesis. A related aspect of the inventionregards a method of preventing or treating loss of sight as aconsequence of neovascularization, which method involves inhibitingangiogenesis by administering to the mammal a translation product of apolynucleotide selected from the group consisting of HMGI genes, MAGgenes and nucleic acid molecules having sequences according to one ofSEQ ID NOS.: 1-19; and then forming a complex between the translationproduct and the polynucleotide, thereby inhibiting angiogenesis.

A nineteenth aspect of the invention relates to a method for inhibitingangiogenesis in a mammal which includes the steps of first administeringto the mammal an antibody to a translation product of a polynucleotideselected from the group consisting of HMGI genes, MAG genes and nucleicacid molecules having sequences according to one of SEQ ID NOS.: 1-19;and then forming a complex between the antibodies and the translationproducts, thereby inhibiting angiogenesis. In one embodiment of theinvented method the antibody is selected from the group consisting ofpolyclonal antibodies, monoclonal antibodies and fragments andderivatives thereof. A related aspect of the invention regards a methodof preventing or treating loss of sight as a consequence ofneovascularization which involves inhibiting angiogenesis byadministering to the mammal an antibody to a translation product of apolynucleotide selected from the group consisting of HMGI genes, MAGgenes and nucleic acid molecules having sequences according to one ofSEQ ID NOS.: 1-19; and then forming a complex between the antibodies andthe translation products, thereby inhibiting angiogenesis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing the genomic structure of the HMGI-C gene,RNA and cDNA and position of the primers used for the RT-PCR.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The mutations that can manifest themselves cytogenetically as structuralchromosome aberrations of region q14-15 of chromosome 12, can be provenwith the help of the methods of the polymerase chain reaction for therapid amplification of 3′ cDNA ends (3′ RACE PCR) and/or forfluorescence in situ-hybridization. It is found that often breaks occurin the third and more rarely in the fourth intron of the HMGI-C gene.The 3′ component of the gene is separated from its original sequence dueto breaks and is substituted by a so-called ectopic DNA sequence. Suchectopic sequences apparently originate in other genes. The fusion geneof the ectopic sequence with parts of the HMGI-C that codes for theDNA-bonding components remains on the resulting derivative of chromosome12 and is expressed as a fusion transcript in the cells, together withthe original transcript. It is not known whether only an expression ofthe gene, e.g. caused by the shift of an enhancer in the area of thegene, can result in the growth of a tumor.

It is remarkable that many of the above tumors have sub-groups for whichthe chromosome changes of band 6p21 are characteristic. The gene forHMGI-Y is located in this band, which, as already indicated above, hasthe highest homologous degree of all known HMG genes compared to theHMGI-C gene, so that mutations of this gene may also play a role in manyof the above tumors.

The agents described in the state of the art that are used for thepurpose of influencing angioneoplasm, i.e. (neo-)angiogenesis,(neo-)vascularization and tumor angiogenesis, and for the purpose ofpreventing blindness due to neo-vascularization as often occurs inconnection with diabetes mellitus, for example, and for the purpose oftreating endometriosis, for the purpose of contraception and tissueregeneration, are characterized in that they use an indirect mechanismto arrive at their final effect.

Indirect mechanism means that the respective agent itself, or effectormolecules formed or activated by this agent, act on the target cells,possibly while using receptors or more or less specific receptor-likestructures, and interfere in the cellular activity without carrying anyspecificity inherent in their own structure which would make it possibleto influence the translation and/or the transcription of the gene or thesequences that are responsible for the respective phenomenon or clinicalpicture.

A number of basic disadvantages can be deducted from this mechanism. Dueto non-specific receptor mechanisms or cross-reactivities of thereceptors or receptor-like structures, said agents often are acceptedinto other tissues as target tissue or target cells. This is why thereare no specific effective locations and therefore significantside-effects must be anticipated. In addition, the influence of saidagents on the reactions within the cell results in a considerabledisturbance which may or may not result in the desired effect in thetarget cell.

Especially problematic is influencing angioneoplasm with state of theart agents. Apart from the hope of spontaneous healing, the only othercommon option in clinical scenarios is to transplant vessels. Theavailability of suitable vessels is a very basic problem.

Influencing angioneoplasm in order to prevent tumor angiogenesis seemsto be a promising prospect for an effective cancer therapy that is beingexamined using suitable, but typically systemic agents. The use of suchsystemic agents, however, is accompanied by corresponding negativeeffects, as described above and as they result from similarlynon-specific radiation therapy.

There are numerous causes for the loss of vision and an equal number ofdifferent treatments are available today. It is a known fact that thevision of patients that suffer from diabetes mellitus is impaired due toneo-vascularization that can result in total blindness. It is possibleto slow vision loss by treating the diabetes mellitus; however, there isan urgent need for an agent that specifically makes it possible to treator prevent blindness due to neo-vascularization, independent of thetherapy for diabetes mellitus.

The side-effects of hormonal agents used for contraceptive purposes aresufficiently known and, despite intensive efforts on the part of thedrug companies, still exist. A central problem in the development oforal contraceptives certainly is the fact that there still is a need fora well tolerable and reliable agent that interrupts a pregnancyfollowing the nidation of the fertilized egg.

Finally, tissue regeneration still is a largely unsolved problem despitesuccesses, above all in the area of skin culture. Typically, complexnutrient solutions are used in order to regenerate at least sometissues. However, the ability to reproduce the process is not alwayscertain, due to the complex media or complex media admixtures that areused whereby complex media or media admixtures are necessary because atargeted admixture of individual factors is rarely successful. Even ifindividual compositions are known that would allow for the regenerationof the respective tissue in the desired manner, side-effects have to beanticipated as well, due to the indirect action of such compositions. Inaddition, the person responsible for regenerating the tissue, as well asthe patient who is to receive the regenerated tissue, might be at greatrisk due to the biological sources required for the regenerationprocess.

The treatment of tumors still poses one of the greatest challenges tomedicine. Despite comprehensive efforts, there are few specifictherapies. Often chemotherapy and radiation therapy offer the onlyalternatives, but they have inherent side-effects that often questionthe use of the therapies as such.

The invention is charged with describing and making available DNAsequences that are suitable, for example, for providing agents for thepurpose of treating diseases or for the purpose of influencingbiological systems while reducing the side-effects that are usuallyassociated with such treatments.

Another object of the invention is to show new uses of sequences of theMAG genes or the genes of the high mobility group proteins, and toprovide agents for the specific treatment of diseases or for influencingbiological systems, while reducing the side-effects that are usuallyassociated with them. The object of the invention is attained through aDNA sequence that is characterized by at least one sequence as shown inSEQ ID NOs: 1 through 19.

In one of the embodiments the DNA sequence corresponds partially orcompletely to the sequence of the HMGI-C gene.

In another embodiment of the invention, parts of the sequences shown inSEQ ID NOs: 1 through 19 make up a part of the DNA sequence of theHMGI-C gene.

It is possible for the DNA sequence to be mutant as compared to the DNAsequence shown in SEQ ID NOs: 1 through 19.

The invention proposes that the DNA sequence primarily has the samesequence as the one shown in SEQ ID NOs: 1 through 19, including therespective complementary strand and modified versions of both strands.

An alternative is that the DNA sequence has a primarily functionallyidentical nucleic acid sequence to the sequences shown in SEQ ID NOs: 1through 19.

In one embodiment, the DNA sequence in accordance with the invention hasat least one sequence that codes for a DNA-bonding part of thecorresponding translation product(s).

An alternative is that the sequence in accordance with the inventiondoes not have a sequence that codes for the protein-bonding part of thecorresponding translation product(s).

In a preferred embodiment, the sequence in accordance with the inventionhas one or several sequences S_(r) which replace(s) or supplement(s) thesequence(s) that code(s) for the protein-bonding part of thecorresponding translation product(s).

In an especially preferred embodiment sequence, S_(r) is selected fromthe group that comprises other sequences of the human genome, sequencesof other (donor) organisms and artificial sequences and combinationsthereof.

In an alternative embodiment, the sequences shown in SEQ ID NOs: 1through 19 are aberrant transcripts of the HMGI-C gene.

In the following paragraphs the above sequences will be called S_(AT).

The invention also describes an expression vector that comprises atleast one transcription promoter that is followed by at least one of theS_(AT) sequences further down.

In addition, the invention comprises a host cell that transfers ortransforms with an expression vector in accordance with the invention.

In a preferred embodiment the host cell is a prokaryotic cell.

In yet another embodiment the host cell is an eukaryotic cell.

In a preferred embodiment the eukaryotic cell is a yeast cell.

In an especially preferred embodiment, the eukaryotic cell is a mammalcell.

In addition, the invention describes a protein that is a translationproduct of one or several of the S_(AT) sequences and/or thecorresponding transcript(s) in native or mutant form and/or in acomplete or fragmented form whereby the translation productglycosylates, is native or mutant and/or is in a complete or fragmentedstate, glycosylates partially or not at all and/or phosphorylates ordoes not phosphorylate and/or is chemically modified or not chemicallymodified.

In yet another aspect the object of the invention is attained throughthe use of at least one of the S_(AT) sequences in accordance with theinvention for the purpose of influencing angioneoplasm.

The invention also describes another aspect that attains the object ofthe invention through the use of a MAG gene for the purpose ofinfluencing angioneoplasm.

Another aspect that attains the object of the invention is the use of atleast one high mobility group protein gene for the purpose ofinfluencing angioneoplasm.

In a preferred embodiment, the high mobility group protein gene isselected from the group that comprises the HMGI-C gene and the HMGI-Ygene.

In the following paragraphs the above genes or groups of genes will bereferred to as G_(G).

It is possible to use sequences that have fundamentally the same nucleicacid sequence as the G_(G) genes.

An alternative is the use of sequences that have essentially the samefunctional nucleic acid sequence as that of the G_(G) genes.

In the following paragraphs, the above defined sequences together withthe above defined G_(G) genes will be referred to as S_(G) sequences.

In another embodiment, the S_(G) sequences have at least one sequencethat codes for a DNA-bonding component of the corresponding translationproduct(s).

In another alternative of the invention the S_(G) sequences and theirderivatives in accordance with the invention do not have any of thesequences that code for the protein-bonding component of thecorresponding translation product(s).

In addition, the S_(G) sequences or derivatives in accordance with theinvention have one or several S_(r) sequences that replace(s) orsupplement(s) the sequence(s) that code(s) for the protein-bondingcomponent of the corresponding translation product(s).

It is possible for the S_(r) sequence to be selected from the group thatcomprises other sequences of the human genome, sequences of other(donor) organisms, and artificial sequences and combinations thereof.

In one embodiment the S_(AT) and S_(G) sequences and their derivativesin accordance with the invention are double-strands and/or a codingand/or non-coding single strand and/or cDNA.

The S_(AT) and S_(G) sequences and their derivatives in accordance withthe invention can be native and/or mutant and/or in a fragmented ornon-fragmented state.

In an embodiment of the invention the S_(AT) and S_(G) sequences andtheir derivatives in accordance with the invention can have at least onepromoter and/or at least one enhancer element and/or at least onetranscription termination element and/or at least one resistance geneand/or at least one additional marking gene.

In one embodiment at least one of the S_(AT) or S_(G) sequences or theirderivatives in accordance with the invention can be cloned in a hostsystem.

In this case the S_(AT) and S_(G) sequences and their derivatives inaccordance with the invention are copied at least once.

In the following paragraphs the above G_(G) genes, the S_(G) sequencesand their derived sequences or the different embodiments will bereferred to as S_(T) sequences.

In accordance with the invention the object of the invention is attainedwith the help of an agent used for the purpose of influencingangioneoplasm and that is comprised of at least one agent M_(S) that isselected from the group that comprises sense DNA, sense RNA, sense cDNA,antisense DNA, antisense RNA and antisense cDNA and combinations thereofas a single strand and/or double strand.

It may be possible for the sequence(s) of the agent(s) M_(S) to benative or mutant and/or in a complete or a fragmented state and/orchemically modified or not chemically modified.

In a preferred embodiment of the invention the sequence of the M_(S)agent(s) correspond(s) to a or several S_(T) or S_(AT) sequence(s)and/or the corresponding transcript(s) that is (are) native or mutantand in a complete or fragmented state.

In the subsequent paragraphs the agents selected from the group thatcomprises the nucleic acid will be referred to as M_(MAKS) agents.

In addition, the object of the invention is attained with the help of anagent used for the purpose of influencing angioneoplasm that comprisesat least one agent M_(P) that is selected from the group that comprisespoly-clonal antibodies, mono-clonal antibodies, and fragments andderivatives thereof.

In this case it is especially preferred if the M_(P) agent acts againsta S_(T) or S_(AT) sequence(s) and/or the corresponding transcriptionproduct(s) that is (are) native or mutant and/or in a complete orfragmented state.

In an especially preferred embodiment the M_(P) agent acts against oneor several translation products of a S_(T) or S_(AT) sequence or severalsequences and/or the corresponding transcript(s) that is (are) native ormutant and/or in a complete or fragmented state and whereby saidtranslation product(s) is (are) native or mutant and/or in a complete orfragmented state and/or is (are) glycosylated, partially glycosylated ornot glycosylated and/or is (are) phosphorylated or not phosphorylated.

In addition, within the framework of the invention, agent M_(P) inaccordance with the invention acts against an antibody or a fragment ofan antibody which in turn acts against one or several S_(T) or S_(AT)sequences and/or the translation product(s) and/or the correspondingtranscription product(s) that is (are) native or mutant and/or in acomplete or fragmented state.

In addition, it is possible for agent M_(P) in accordance with theinvention to act against an antibody or a fragment of the antibody whichin turn acts against one or several translation products of one orseveral of the S_(T) or S_(AT) sequences and/or the correspondingtranscript(s) that is (are) native or mutant and/or in a complete orfragmented state and whereby said translation product(s) is (are) nativeor mutant and/or in a complete or fragmented state and/or is (are)glycosylated, partially glycosylated or not glycosylated and/or is (are)phosphorylated or not phosphorylated.

In the subsequent paragraphs the above agents selected from the group ofantibodies and fragments and their derivatives will be referred to asM_(MAKP) agents.

In accordance with the invention the object is also attained with thehelp of an agent used for the purpose of influencing angioneoplasm thatis comprised of at least one translation product of one or several S_(T)or S_(AT) sequences and/or the corresponding transcript(s) that is (are)native or mutant and/or in a complete or fragmented state and wherebysaid translation product(s) is (are) native or mutant and/or in acomplete or fragmented state and/or is (are) glycosylated, partiallyglycosylated or not glycosylated and/or is (are) phosphorylated or notphosphorylated and/or is (are) chemically modified or not chemicallymodified.

In the subsequent paragraphs the above translation product will bereferred to as translation product TP.

Finally the object of the invention is attained with the help of anagent in accordance with the invention that is used for the purpose ofinfluencing angioneoplasm and that is comprised of at least oneexpression inhibitor and/or at least an agent that stimulates theexpression.

Especially preferred in this case is when the expression inhibitorand/or the agent that stimulates the expression has a higher degree ofspecificity for one or several of the S_(T) or S_(AT) sequences comparedto other genes of the respective genetic system.

Especially preferred is a scenario in which the expression inhibitorand/or the agent that stimulates the expression is specific for one orseveral S_(T) or S_(AT) sequences.

The above described expression inhibitor will be referred to asexpression inhibitor I and the above described agent that stimulates theexpression will be referred to as agent ES.

One use of the agent in accordance with the invention for the purpose ofinfluencing angioneoplasm concerns angiogenesis.

Especially preferred is an effect which reduces and/or preventsangiogenesis.

In an alternative, angiogenesis can be stimulated.

Especially preferred is an embodiment in which the influence on theangioneoplasm affects tumor angiogenesis.

In addition, one use of the agents in accordance with the invention forthe purpose of influencing angioneoplasm concerns vascularization.

Especially preferred in this case is an embodiment in whichvascularization is stimulated.

As alternative is for vascularization to be reduced or prevented.

Another aspect of the invention concerns the treatment and/or preventionof blindness due to neo-vascularization while using at least one of theagents in accordance with the invention for the purpose of influencingangioneoplasm.

Finally another aspect of the invention is to improve the vessel supplyof heart muscle tissue with cardiac infarction damage while using atleast one agent in accordance with the invention for the purpose ofinfluencing angioneoplasm.

It is possible to use the agent in accordance with the invention inhumans and/or animals.

In addition, it is possible to use the agent for therapeutic and/ordiagnostic applications in humans and/or animals.

In addition, it is possible to use it in vitro.

Another use in accordance with the invention of at least one of theagents in accordance with the invention is its/their use in theproduction of a drug for therapeutic and/or diagnostic applications forthe purpose of influencing angioneoplasm.

Another aspect of the invention describes a kit for the purpose ofinfluencing angioneoplasm that contains at lest one M_(MAKS) and/or oneM_(MAKP) agent.

It is possible for the kit to contain at least one translation productof one or several of the S_(T) or S_(AT) sequences and/or thecorresponding transcript(s) that is (are) native or mutant and/or in acomplete or fragmented state and whereby said translation product(s) is(are) native or mutant and/or in a complete or fragmented state and/oris (are) glycosylated, partially glycosylated or not glycosylated and/oris (are) phosphorylated or not phosphorylated and/or is (are) chemicallymodified or not chemically modified.

At least one expression inhibitor I and/or at least one agent ES thatstimulates the expression is contained in one embodiment of the kit.

In an especially preferred embodiment of the invention the kit containsat least one M_(MAKS) and/or at least one M_(MAKP) agent and/or onetranslation product TP and/or at least one expression inhibitor I and/orat least an agent ES that stimulates the expression.

In an especially preferred embodiment the kit can be used for thepurpose of influencing tumor angiogenesis.

In another embodiment the kit is used for the purpose of influencingangiogenesis.

It also is possible to use the kit for the purpose of influencingvascularization.

An alternative is to use the kit for the purpose of inhibitingangioneoplasm.

An alternative is to use the kit for the purpose of stimulatingangioneoplasm.

Finally, it is possible to use the kit for the purpose of treatingand/or preventing blindness due to neo-vascularization.

In addition, it is possible to use the kit in accordance with theinvention for the purpose of improving the vessel supply of heart muscletissue damaged by cardiac infarction.

The kit may be used for therapeutic treatment and/or for diagnosispurposes.

It is possible to use the kit in humans and/or animals.

Finally it is possible to use the kit in in vitro systems.

The object is attained in accordance with the invention through the useof at least one of the sequences S_(AT) in accordance with the inventionfor the treatment of endometriosis.

In a broader aspect in which the object is attained, the inventionconcerns the use of a MAG gene for the treatment of endometriosis.

A further aspect of the invention in which the object is attainedconcerns the use of at least one high mobility group protein gene forthe treatment of endometriosis.

In a preferred embodiment, it is provided that the high mobility groupprotein gene is selected from the group which comprises the HMGI-C geneand the HMGI-Y gene.

The above genes and/or groups of genes are designated below as genesG_(G).

It can be provided that sequences are used with essentially the samesequence of nucleic acid as the gene G_(G).

In an alternative, sequences can be used with a nucleic sequence whichis essentially the same functionally as that of the gene G_(G).

The above-defined sequences together with the above-defined genes G_(G)will be designated below as sequences S_(G).

In a further embodiment, it is provided that the sequences S_(G) have atleast one sequence which codes for a DNA binding portion of thecorresponding translation product(s).

In a further alternative of the invention, it is provided that thesequences S_(G) and derivatives thereof do not have any sequence whichcodes for the protein-binding portion of the corresponding translationproduct(s).

It can further be provided that the sequences S_(G) or derivativesthereof in accordance with the invention have one or several sequencesS_(r) which replace the sequence(s) which code for the protein-bindingportion of the corresponding translation product(s).

It is possible in this case for the sequence S_(r) to be selected fromthe group which comprises other sequences of the human genome, sequencesof other (donor) organisms, and artificial sequences and combinationsthereof.

In one embodiment, it is provided that the sequences S_(AT) or S_(G), aswell as derivatives thereof in accordance with the invention are presentas double-strand and/or coding and/or non-coding single strand and/orcDNA.

It can further be provided that the sequences S_(AT) or S_(G) as well asderivatives thereof in accordance with the invention are present innative and/or mutant and/or fragmented or unfragmented forms.

In one embodiment of the invention, the sequences S_(AT) or S_(G) aswell as derivatives thereof in accordance with the invention have atleast one enhancer element and/or at least one transcription terminationelement and/or at least one resistance gene and/or at least one othermarking gene.

In one embodiment, at least one of the sequences S_(AT) or S_(G) orderivatives thereof in accordance with the invention are present asclones in a host system.

It is provided In this case that the sequences S_(AT) or S_(G) orderivatives thereof in accordance with the invention are present in atleast one copy.

The aforementioned gene G_(G), the sequences S_(G), and the sequencesderived therefrom or the various embodiments are designated below assequences S_(T).

The object is attained in accordance with the invention through an agentfor the treatment of endometriosis which comprises at least one agentM_(S), which is selected from the group which comprises sense DNA, senseRNA, sense cDNA, antisense DNA, antisense RNA, and antisense cDNA, andcombinations thereof as individual strands and/or double strands.

It can be provided that the sequence(s) of the agent(s) M_(S) arepresent in native or mutant form and/or complete or fragmented and/orchemically modified or not chemically modified.

In a preferred embodiment, the sequence of the agent(s) M_(S) correspondto sequence(s) S_(T) or the corresponding transcript(s) which arepresent in native or mutant form, complete or fragmented.

The above agents selected from the group comprising the nucleic acidsshall be referred to below as agents M_(SS).

The object is further attained through an agent for the treatment ofendometriosis which comprises at least one agent M_(P) which is selectedfrom the group which comprises polyclonal antibodies, monoclonalantibodies, and fragments and derivatives of the same.

It is especially preferred In this case that the agent M_(P) be directedagainst a sequence(s) S_(T) or S_(AT) and/or the correspondingtranscription product(s) which are present in native or mutant formand/or complete or fragmented.

In a particularly preferred embodiment, the agent M_(P) acts against oneor several translation products of a sequence or several sequences S_(T)or S_(AT) and/or of the corresponding transcript(s) which are present innative or mutant form and/or complete or fragmented and whereby saidtranslation product(s) are present in native or mutant form and/orcomplete or fragmented and/or glycosylated, partially glycosylated, ornot glycosylated and/or phosphorylated or not phosphorylated.

In addition, it is within the framework of the present invention thatthe agent M_(P) in accordance with the invention acts against anantibody or a fragment thereof which in turn acts against one or moresequences S_(T) or S_(AT) and/or the corresponding transcriptionproduct(s) which are present in native or mutant form and/or complete orfragmented.

In addition, it can be provided that the agent in accordance with theinvention act against an antibody or a fragment of the same which inturn acts against one or several translation products of one or severalsequences S_(T) or S_(AT) and/or corresponding transcript(s) which arepresent in native or mutant form and/or complete or fragmented andwhereby said translation product(s) are present in native or mutant formand/or complete or fragmented and/or glycosylated, partiallyglycosylated or not glycosylated and/or phosphorylated or notphosphorylated.

The aforementioned agent selected from the group comprised of antibodiesand fragments and derivatives of the same will be designated below asagent M_(MAKP).

The object is attained in accordance with the invention through an agentwhich comprises at least one translation product of one or severalsequences S_(T) or S_(AT) and/or the corresponding transcript(s) whichare present in native or mutant form and/or complete or fragmented andwhereby said translation product(s) are present in native or mutant formand/or complete or fragmented and/or glycosylated, partiallyglycosylated or not glycosylated and/or phosphorylated or notphosphorylated and/or chemically modified or not chemically modified.

The translation product described above shall be designated below astranslation product TP.

Finally, the object is attained by means of an agent in accordance withthe invention for the treatment of endometriosis which comprises atleast one expression inhibitor and/or at least one agent whichstimulates the expression.

It is particularly preferred In this case that the expression inhibitorand/or the expression stimulating agent have an elevated specificity forone or more of the sequences S_(T) or S_(AT) compared with other genesof the genetic system in question.

It is quite particularly preferred In this case that the expressioninhibitor and/or the expression-stimulating agent be specific for one ormore sequences S_(T) or S_(AT).

One application in accordance with the invention provides that at leastone of the agents in accordance with the invention is used for thetreatment of endometriosis in humans or in animals.

In one embodiment, use is indicated for therapeutic and/or diagnosticapplication in humans and/or in animals.

A further application in accordance with the invention provides the invitro application of at least one of the agents in accordance with theinvention.

Finally, an application in accordance with the invention can provide forthe application of at least one of the agents in accordance with theinvention for the manufacture of a drug for the therapeutic and/ordiagnostic application in the treatment of endometriosis.

In a further aspect, the invention concerns a kit for the treatment ofendometriosis which contains at least an agent M_(MAKS) and/or an agentM_(MAKP).

It is possible for a kit to contain a translation product of one or moreof sequences S_(T) or S_(AT) and/or of the corresponding transcript(s)which are present in native or mutant form and/or complete or fragmentedand whereby said translation product(s) are present in native or mutantform and/or complete or fragmented and/or glycosylated, partiallyglycosylated or not glycosylated and/or phosphorylated or notphosphorylated and/or chemically modified or not chemically modified.

In one embodiment of the kit, at least one expression inhibitor I and/orone expression-stimulating agent ES are contained.

In a particularly preferred embodiment, it is provided that at least oneagent M_(MAKS) and/or at least one agent M_(MAKP) and/or at least onetranslation product TP and/or at least one expression inhibitor I and/orat least one expression-stimulating agent ES is contained.

The kit can be used for therapeutic treatment and/or for diagnosis.

It is provided that the kit will be used with humans and/or animals.

Finally, the kit can also be used in in vitro systems.

The object can be attained in accordance with the invention through theuse of at least one of the sequences S_(AT) for contraception.

In a broader aspect in which the object is attained, the inventionconcerns the use of a MAG gene for contraception.

Another aspect of the invention in which the object is attained concernsthe use of at least one high mobility group protein gene forcontraception.

In a preferred embodiment, it is provided that the high mobility groupprotein gene is selected from the group which comprises the HMGI-C geneand the HMGI-Y gene.

The above gene or group of genes are designated below as genes G_(G).

It can be provided that sequences are used with essentially the samenucleic acid sequence as the genes G_(G).

In an alternative, sequences can be used with nucleic acid sequencewhich is, in essence, functionally the same as that of genes G_(G).

The sequences defined above, together with genes G_(G), which arelikewise defined above, shall be designated from this point forward assequences S_(G).

In a further embodiment, it is provided that the sequences S_(G) have atleast one sequence which code for a DNA-binding portion of thecorresponding translation product(s).

In a further alternative of the invention, it is provided that thesequences S_(G) and derivatives thereof have no sequence which codes forthe protein-binding portion of the corresponding translation product(s).

Furthermore, it can be provided that the sequences S_(G) or derivativesthereof in accordance with the invention have one or more sequencesS_(r) which replace or supplement that sequence or those sequences whichcode for the protein-binding portion of the corresponding translationproduct(s).

It is possible In this case for the sequences S_(r) to be selected fromthe group which comprises the other sequences of the human genome,sequences of other (host) organisms, and artificial sequences andcombinations thereof.

In one embodiment, it is provided that the sequences S_(AT) and S_(G) aswell as derivatives thereof in accordance with the invention are presentas double strand and/or coding and/or non-coding single strand and/orcDNA.

Furthermore, it can be provided that the sequences S_(AT) and S_(G) aswell as derivatives thereof in accordance with the invention are presentas natives and/or mutants and/or fragmented or not fragmented.

In one embodiment of the invention, the sequences S_(AT) and S_(G) aswell as derivatives thereof have at least one promoter and/or at leastone enhancer element and/or at least one transcription terminationelement and/or at least one resistance gene and/or at least one othermarking gene.

In one embodiment, at least one of the sequences S_(AT) or S_(G) orderivatives in accordance with the invention are present as clones in ahost system.

It is provided In this case that the sequences S_(AT) and S_(G) as wellas derivatives thereof in accordance with the invention are present inat least one copy.

The aforementioned genes G_(G), the sequences S_(G), and the sequencesderived therefrom or from the various embodiments are designated belowas sequences S_(T).

The object is attained in accordance with the invention through an agentfor contraception which comprises at least one agent M_(S) which isselected from the group which comprises sense DNA, sense RNA, sensecDNA, antisense DNA, antisense RNA, and antisense cDNA and combinationsthereof as single strand and/or as double strand.

It can be provided that the sequence(s) of the agent(s) M_(S) arepresent in native or mutant form and/or complete or fragmented and/orchemically modified or not chemically modified.

In a preferred embodiment, the sequence of the agent(s) M_(S) correspondto a sequence(s) S_(T) or S_(AT) and/or to the correspondingtranscript(s) which is present in native or mutant form, complete orfragmented.

The aforementioned agents derived from the group comprising nucleicacids shall be designated below as agent M_(MAKS).

The object can also be attained through an agent for contraception whichcomprises at least one M_(S) which is selected from the group whichcomprises polyclonal antibodies, monoclonal antibodies, and fragmentsand derivatives of the same.

It is particularly preferred In this case that the agent M_(P) actagainst the sequence(s) S_(T) or S_(AT) and/or the correspondingtranscription product(s) which are present in native or mutant formand/or complete or fragmented.

In a particularly preferred embodiment, the agent M_(P) acts against oneor more translation products of one or more sequences S_(T) or S_(AT)and/or of the corresponding transcript(s) which are present in native ormutant form and/or complete or fragmented and whereby said translationproduct(s) are present in native or mutant form and/or compete orfragmented and/or glycosylated, partially glycosylated, or notglycosylated and/or phosphorylated or not phosphorylated.

Furthermore, it is within the framework of the present invention thatthe agent M_(P) in accordance with the invention acts against anantibody or a fragment of the same which in turn acts against asequence(s) S_(T) or S_(AT) and/or the corresponding transcriptionproduct(s) are present in native or mutant form and/or complete orfragmented.

Furthermore, it can be provided that the agent M_(P) in accordance withthe invention acts against an antibody or a fragment of the same whichin turn acts against one or several translation products of one or moresequences S_(T) or S_(AT) and/or of the corresponding transcript(s)which are present in native or mutant form and/or complete orfragmented, and whereby said translation product(s) are present innative or mutant form and/or complete or fragmented and/or glycosylated,partially glycosylated, or not glycosylated and/or phosphorylated or notphosphorylated.

The above-indicated agents selected from the group comprising theantibodies and fragments and derivatives of the same will be designatedbelow as agents M_(MAKP).

The object is attained in accordance with the invention through an agentfor contraception which comprises at least one translation product(s) orone or more sequences S_(T) or S_(AT) and/or of the correspondingtranscript(s) which are present in native or mutant form and/or completeor fragmented and whereby said translation product(s) are present innative or mutant form and/or complete or fragmented and/or glycosylated,partially glycosylated, or not glycosylated and/or phosphorylated or notphosphorylated and/or chemically modified or not chemically modified.

The above described translation product is designated below astranslation product TP.

Finally, the object is attained through an agent in accordance with theinvention for contraception which comprises at least one expressioninhibitor and/or at least one agent which stimulates the expression.

It is particularly preferred in this case that the expression inhibitorand/or the agent which stimulates the expression have an elevatedspecificity for one or more of the sequences S_(T) or S_(AT) comparedwith other genes of the particular genetic system.

It is particularly preferred in this case that the expression inhibitorand/or the agent which stimulates the expression be specific for one ormore sequences S_(T) or S_(AT).

The above described expression inhibitor will be designated below asexpression inhibitor I and the above described expression-stimulatingagent will be designated below as ES.

An application in accordance with the invention provides the applicationof at least one of the agents in accordance with the invention for oralcontraception.

A further application in accordance with the invention provides the useof at least one of the agents in accordance with the invention for localcontraception.

It can be provided that the application is for humans and/or foranimals.

In an alternative, the application concerns the therapeutic applicationfor humans and/or for animals.

A further application in accordance with the invention of at least oneof the agents in accordance with the invention concerns the manufactureof a drug for therapeutic application.

In an additional application in accordance with the invention, theaspect through which the object is attained concerns the invention of akit for contraception which contains at least one agent M_(MAKS) and/orat least one agent M_(MAKP).

It is possible for a kit to contain at least one translation product ofone or more of the sequences S_(T) or S_(AT) and/or of the correspondingtranscript(s) which are present in native or mutant form and/or completeor fragmented and whereby said translation product(s) in native ormutant form and/or complete or fragmented and/or glycosylated, partiallyglycosylated, or not glycosylated and/or phosphorylated or notphosphorylated and/or chemically modified or not chemically modified.

In one embodiment of the kit, at least one expression inhibitor I and/orat least one expressing-stimulating agent ES is contained.

In a particularly preferred embodiment, it is provided that at least oneagent M_(MAKS) and/or at least one agent M_(MAKP) and/or at least onetranslation product TP and/or at least one expression inhibitor I and/orat least one expression-stimulating agent ES be contained in the kit.

In a quite particularly preferred embodiment, the kit can be used fororal contraception.

Furthermore, it is possible for the kit to be used for localcontraception.

The kit can be used for therapeutic treatment and/or for diagnosis.

It is provided that the kit is used for humans and/or animals.

Finally, the kit can also be used in in vitro systems.

In a further aspect, the invention concerns a process of contraceptionwhich provides that at least one agent is administered which is selectedfrom the group which contains sense DNA, sense RNA, sense cDNA,antisense DNA, antisense RNA, and antisense cDNA and combinationsthereof as a single strand and/or as a double strand and whereby thesequence of the agent selected from the group corresponds to thesequence(s) S_(T) and/or S_(AT) and/or the corresponding transcript(s)which is (are) present in native or mutant form and/or complete orfragmented.

In addition, the invention represents a process for contraception whichprovides for the administration of at least one agent which is selectedfrom the group which contains polyclonal antibodies, monoclonalantibodies, and fragments and derivatives of the same and whereby theagent selected from the group acts against the sequence(s) S_(T) and/orS_(AT) and/or in the direction opposite to the correspondingtranscript(s) which are present in native or mutant form and/or completeor fragmented.

In a further aspect of the invention, a process for contraception issuggested which provides that at least one agent be administered whichis selected from the group which contains polyclonal antibodies,monoclonal antibodies, and fragments and derivatives of the same andwhereby the agent selected from the group acts against one or more ofsequences S_(T) and/or SAT and/or of the corresponding transcript(s)which is (are) present in native or mutant form and/or complete orfragmented and whereby said translation product(s) is (are) present innative or mutant form and/or complete or fragmented and/or glycosylated,partially glycosylated, or not glycosylated and/or phosphorylated or notphosphorylated.

In addition, the invention suggests a procedure for contraception whichis characterized by the fact that at least one agent is administeredwhich is a translation product of one or more sequences S_(T) and/orS_(AT) and/or of the corresponding transcript(s) which is (are) presentin native or mutant form and/or complete or fragmented and whereby saidtranslation product(s) is (are) present in native or mutant form and/orcomplete or fragmented and/or glycosylated, partially glycosylated, ornot glycosylated and/or phosphorylated or not phosphorylated and/orchemically modified or not chemically modified.

In preferred embodiments of the process in accordance with the inventionfor contraception, said agent is administered orally.

In a further preferred embodiment, it is provided that said agent isadministered periodically.

An additional alternative of the procedure in accordance with theinvention provides that said agent is administered following conception.

The object is attained in accordance with the invention through the useof at least one of sequences S_(AT) for tissue regeneration.

In a further aspect through which the object is attained, the inventionconcerns the use of a MAG gene for tissue regeneration.

Another aspect of the invention in which the object is attained concernsthe use of at least one high mobility group protein gene for tissueregeneration.

In a preferred embodiment, it is provided that the high mobility groupprotein gene is selected from the group which comprises the HMGI-C geneand the HMGI-Y gene.

The above genes or groups of genes are designated below as gene G_(G).

It can be provided that sequences are used with essentially the samenucleic acid sequence as genes G_(G).

In an alternative, sequences are used with a nucleic acid sequence whichis essentially the same functionally as that of the genes G_(G).

The above-defined sequences together with the above-defined genes G_(G)shall be designated below as sequences S_(G).

In a further embodiment, it is provided that the sequences S_(G) have atleast one sequence which codes for a DNA-binding portion of thecorresponding translation product(s).

In a further alternative of the invention, it is provided that thesequences S_(G) and derivatives thereof do not have any sequence whichcodes for the protein-binding portion of the corresponding translationproduct(s).

Furthermore, it can be provided that the sequences S_(G) or derivativesthereof in accordance with the invention have one or more sequencesS_(r) which replace or supplement that sequence or those sequences whichcode for the protein-binding portion of the corresponding translationproduct(s).

It is possible In this case for the sequence S_(r) to be selected fromthe group which comprises other sequences of the human genome, sequencesof other (host) organisms and artificial sequences and combinationsthereof.

In one embodiment, it is provided that the sequences S_(AT) or S_(G) andderivatives in accordance with the invention thereof are present asdouble strand and/or coding and/or non-coding single strand and/or cDNA.

Furthermore, it can be provided that the sequences S_(AT) of S_(G) andthe derivatives thereof in accordance with the invention are present asnative and/or mutant and/or fragmented or not fragmented.

In one embodiment of the invention, the sequences S_(AT) or S_(G) andderivatives thereof in accordance with the invention can have at leastone promoter and/or at least one enhancer element and/or at least onetranscription termination element and/or at least one resistance geneand/or at least one other marking gene.

In one embodiment, at least one of the sequences S_(AT) or S_(G) orderivatives thereof in accordance with the invention are present asclones in a host system.

It is provided In this case that the sequences S_(AT) or S_(G) andderivatives thereof in accordance with the invention are present in atleast one copy.

The above genes G_(G), the sequences S_(G), and the sequences derivedtherefrom or the various embodiments will be designated below assequences S_(T).

The object is attained in accordance with the invention through an agentfor tissue regeneration which comprises at least one agent M_(S) whichis selected from the group which comprises sense DNA, sense RNA, sensecDNA, antisense DNA, antisense RNA, and antisense cDNA and combinationsthereof as single strand or double strand.

It can be provided that the sequence(s) of agent(s) M_(S) are present innative or mutant form and/or complete or fragmented and/or chemicallymodified or not chemically modified.

In a preferred embodiment, the sequence of agent(s) M_(S) correspond toa sequence(s) S_(T) or S_(AT) and/or to the corresponding transcript(s)which are present in native or mutant form, complete or fragmented.

The above agents selected from the group comprised on nucleic acids aredesignated below as agents M_(SS).

Furthermore, the object is attained in accordance with the inventionthrough an agent for regeneration of tissue which comprises at least oneagent M_(P) which is selected from the group which comprises polyclonalantibodies, monoclonal antibodies, and fragments and derivatives of thesame.

It is particularly preferred In this case that the agent M_(P) bedirected against a sequence(s) S_(T) or S_(AT) and/or the correspondingtranscription product(s) which are present in native or mutant formand/or complete or fragmented.

In a particularly preferred embodiment, the agent M_(P) acts against oneor more translation products of a sequence or several sequences S_(T) orS_(AT) and/or of the corresponding transcripts which are present innative or mutant form and/or complete or fragmented and whereby saidtranslation product(s) are present in native or mutant form and/orcomplete or fragmented and/or glycosylated, partially glycosylated, ornot glycosylated and/or phosphorylated or not phosphorylated.

Furthermore, it is within the framework of the invention for the agentM_(P) in accordance with the invention to be directed against anantibody or a fragment thereof which in turn acts against a sequence(s)S_(T) or S_(AT) and/or the corresponding transcription product(s) whichare present in native or mutant form and/or complete or fragmented.

Furthermore, it can be provided that the agent M_(P) in accordance withthe invention acts against an antibody or a fragment thereof which inturn acts against one or more translation product(s) of a sequence(s)S_(T) or S_(AT) and/or of the corresponding transcript(s) which arepresent native or mutated and/or complete or fragmented and whereby saidtranslation product(s) are present in native or mutant form and/orcomplete or fragmented and/or glycosylated, partially glycosylated, ornot glycosylated and/or phosphorylated or not phosphorylated.

The above agents selected from the group comprising the antibodies andfragments and derivatives of the same are designated below as agentsM_(MAKP).

The object is attained in accordance with the invention through an agentfor the regeneration of tissue which comprises at least one translationproduct of a sequence(s) S_(T) or S_(AT) and/or of the correspondingtranscript(s) which is (are) present in native or mutant form and/orcomplete or fragmented and whereby said translation product(s) is (are)present in native or mutant form and/or complete or fragmented and/orglycosylated, partially glycosylated, or not glycosylated and/orphosphorylated or not phosphorylated and/or chemically modified or notchemically modified.

The above-described translation product is designated below astranslation product TP.

Finally, the object is attained through an agent in accordance with theinvention for regeneration of tissue which comprises at least one agentwhich stimulates the expression.

It is particularly preferred In this case that compared with other genesof the particular genetic system, the agent which stimulates theexpression have an elevated specificity for one or more sequences S_(T)or S_(AT).

It is quite particularly preferred In this case that the agent whichstimulates the expression be specific for a sequence or severalsequences S_(T) or S_(AT).

The above-described agent which stimulates the expression will bedesignated below as the expression stimulating agent ES.

An application in accordance with the invention of at least one of theagents in accordance with the invention for regeneration of tissueprovides that the tissue to be regenerated is selected from the groupwhich comprises degenerative tissue, traumatically damaged tissue, andtissue damaged by other means.

An application of at least one of the agents in accordance with theinvention for the regeneration of tissue is particularly preferred ifthe tissue to be regenerated is mesenchymal tissue.

It is quite particularly preferred that the mesenchymal tissue beselected from the group which comprises cartilage, muscle, fat, andconnective and support tissue.

A further application in accordance with the invention concerns theapplication of at least one of the agents in accordance with theinvention for the regeneration of tissue in vivo.

The invention suggests that the use take place in humans and/or inanimals.

Furthermore, the use for therapeutic application in humans and/or inanimals is provided.

A further aspect of the invention concerns the use of at least one ofthe agents in accordance with the invention for regeneration of tissuein vitro.

It is particularly preferred that the application take place in or oncultures which are selected from the group which comprises cellcultures, tissue cultures, organ cultures, and combinations thereof.

In a further application in accordance with the invention, the agent inaccordance with the invention is provided for the manufacture of a drugfor therapeutic application in the regeneration of tissue.

In a further aspect, the invention concerns a kit for the regenerationof tissue which contains at least an agent M_(MAKS) and/or an agentM_(MAKP).

It is possible for a kit to contain at least one translation product ofone or several of the sequences S_(T) or S_(AT) and/or of thecorresponding transcript(s) which is present in native or mutant formand/or complete or fragmented and whereby said translation product(s)are present in native or mutant form and/or complete or fragmentedand/or glycosylated, partially glycosylated, or not glycosylated and/orphosphorylated or not phosphorylated and/or chemically modified or notchemically modified.

In one embodiment at least one expression-stimulating agent ES iscontained.

In a particularly preferred embodiment, it is provided that at least oneagent M_(MAKS) and/or at least one agent M_(MAKP) and/or at least onetranslation product TP and/or at least one expression-stimulation agentES is contained in the kit in accordance with the invention.

The kit can be used for therapeutic treatment and/or for diagnosis.

Furthermore, it can be provided that the kit is used in vivo.

It is provided that the kit is used for humans and/or for animals.

Finally, the kit can also be used in in vitro systems.

It is particularly preferred In this case if the kit is used in or oncultures which are selected from the group which comprises cellcultures, tissue cultures, organ cultures, and combinations of the same.

In a further aspect, the invention concerns a process for theregeneration of tissue in which at least one of the sequences S_(T) orS_(AT) is expressed in the tissue which is to be regenerated.

In a further aspect through which the object is attained, the inventionconcerns a procedure which comprises the following steps:

a) Preparation of cells which are designated target cells;b) Introduction of at least one of the sequences S_(T) or S_(AT) intothe target cells;c) Induction of the expression by at least one of the sequences S_(T) orS_(AT) into the target cells; and optionallyd) Cultivation of the target cells.

It can be provided that in the cultivation of the target cells at leastone of the sequence S_(T) or S_(AT) is expressed.

In a preferred embodiment, at least one of the sequences S_(T) or S_(AT)is introduced in vitro into the target cells by means of a procedurewhich is selected from the group which comprises transfection,microinjection, electroporation, gene transfer by means of liposomes,and transformation brought about through agents.

In addition, it can be provided that the expression and/or induction ofthe expression is influenced by at least one agent M_(MAKS) and/or atleast one agent M_(MAKP) and/or at least one translation TP and/or atleast one expressing-stimulating agent ES.

In one embodiment, the target cells can originate from an animalorganism including from a human.

In another embodiment, it is provided that the target cells originatefrom an animal organism but not from a human.

It can be provided that the target cells represent a different cell typethan the cell types contained in the tissue which is to be regenerated.

Alternatively, it can be provided that the cell types represent a celltype such as is contained in the tissue which is to be regenerated.

It is preferred that the target cells (de-)differentiate intopluripotent stem cells under the influence of at least one of thesequences S_(T) or S_(AT).

In a preferred embodiment of the procedure, the target cells areco-cultured with other cells and/or cell types.

It is particularly preferred In this case that the cells and/or celltypes used for co-cultivation influence the differentiation state of thetarget cells.

In a further embodiment, the target cells are prepared through thewithdrawal of material from an organism whereby the material is selectedfrom the group which comprises biological fluids containing cells,individual cells, tissue, and organs.

It is furthermore provided that following introduction of at least oneof the sequences S_(T) or S_(AT) in the target cells, these target cellsare introduced into an animal organism.

It is further provided that following introduction of at least one ofthe sequences S_(T) or S_(AT) into the target cells, expression beinduced in the target cells before the target cells are introduced intoan animal organism.

In an alternative, following the introduction of at least one of thesequences S_(T) or S_(AT) into the target cells their expression isinduced in the target cells after which the target cells were introducedinto an animal organism.

In a preferred embodiment, the target cells which were introduced intoan animal organism are in a differentiated and/ordifferentiation-competent condition.

In a quite particularly preferred embodiment, the animal organism is ahuman organism.

It is provided that the organism in which the target cells areintroduced is identical with the organism from which the target cellswere taken.

Alternatively, it is provided that the organism in which the targetcells are introduced are different from the organism from which thetarget cells originate.

It can be provided that at least one of the sequences S_(T) or S_(AT) isintroduced into the tissue in the organism which is to be regeneratedand/or the corresponding cells.

In a particularly preferred embodiment, it is provided that at least oneof the sequences S_(T) or S_(AT) is introduced into the tissue to beregenerated and/or the corresponding cells with the use ofgene-therapeutic procedures.

In one embodiment of the procedure in accordance with the invention, theintroduced sequence S_(T) or S_(AT) is expressed.

It is particularly preferred that the expression of the introducedsequence S_(T) or S_(AT) be influenced by at least one agent M_(MAKS)and/or at least one agent M_(MAKP) and/or at least one translationproduct TP and/or one expression-stimulating agent ES.

A particularly preferred embodiment in accordance with the inventionprovides that the tissue to be regenerated is selected from the groupwhich comprises mesenchymal tissue.

A further quite particularly preferred embodiment of the procedure inaccordance with the invention provides that the mesenchymal tissue isselected from the group which comprises cartilage, muscle, fat, andconnective and support tissue.

In an additional aspect, the invention while achieving the objectconcerns the use of at least one of the sequences S_(AT) in accordancewith the invention for the treatment of tumor diseases.

In a further aspect in which the object is attained, the inventionconcerns the use of a MAG gene for the treatment of tumor diseases.

Another aspect of the invention in which the object is attained concernsthe use of at least one high mobility group protein gene for thetreatment of tumor diseases.

In a preferred embodiment, it is provided that the high mobility groupprotein gene is selected from the group which comprises the HMGI-C geneand the HMGI-Y gene.

The above genes or groups of genes are designated below as G_(G).

It can be provided that sequences are used with essentially the samesequence of nucleic acids as the genes G_(G).

In an alternative, sequences can be used with a sequence of nucleicacids which is, in essence, functionally the same as that of the genesG_(G).

The above-defined sequences together with the above-defined genes G_(G)will be designated below as sequences S_(G).

In an additional embodiment, it is provided that the sequences S_(G)have at least one sequence which codes for a DNA-binding portion of thecorresponding translation product(s).

In an additional alternative of the invention, it is provided that thesequences S_(G) in accordance with the invention and derivatives thereofhave no sequence which codes for the protein-binding portion of thecorresponding translation product(s).

Furthermore, it can be provided that the sequences S_(G) or derivativesin accordance with the invention thereof have one or more sequencesS_(r) which replace or supplement that sequence or those sequences whichcode for the protein-binding portion of the corresponding translationproduct or products.

It is possible In this case for the sequence S_(r) to be selected fromthe group which comprises other sequences of the human genome, sequencesof other (donor) organisms, and artificial sequences and combinationsthereof.

In one embodiment, it is provided that the sequences S_(AT) and S_(G),as well as derivatives thereof in accordance with the invention arepresent as a double strand and/or a coding and/or non-coding singlestrand and/or cDNA.

Furthermore, it can be provided that the sequences S_(AT) and S_(G) aswell as derivatives thereof in accordance with the invention are presentas natives and/or mutants and/or are fragmented or not fragmented.

In one embodiment of the invention, the sequences S_(AT) and S_(G) aswell as derivatives thereof in accordance with the invention have atleast one promoter and/or at least one enhancer element and/or at leastone transcription termination element and/or at least one resistancegene and/or at least one other marking gene.

In one embodiment, at least one of the sequences S_(AT) or S_(G) orderivatives thereof in accordance with the invention are present asclones in a host system.

It is provided in this case that the sequences S_(AT) and S_(G) as wellas derivatives thereof in accordance with the invention are present inat least one copy.

The above genes G_(G), the sequences S_(G), and the sequences ordifferent embodiment forms derived therefrom will be designated below assequences S_(T).

According to the invention, the object is attained by an agent fortreating tumor diseases that includes at least one M_(SAT) agentselected from the group that includes sense DNA, sense RNA, sense cDNA,antisense DNA, antisense RNA and antisense cDNA, and combinationsthereof, as a single strand and/or as a double strand, whereby thesequence of the M_(SAT) agent corresponds to one or more of the S_(AT)or S_(T) sequences or to the corresponding transcript(s).

In a preferred form of embodiment it is provided that the sequence ofthe S_(AT) or S_(T) sequences or of the corresponding transcripts ispresent in native or mutant form and/or complete or as a fragment.

In a further form of embodiment it can be provided that the sequence ofthe M_(SAT) agent is present in native or mutant form and/or complete oras a fragment and/or chemically modified or not chemically modified.

Furthermore the invention suggests an agent for treating tumor diseasesthat includes at least one M_(PAT) agent selected from the group thatincludes polyclonal antibodies, monoclonal antibodies, and fragments andderivatives thereof, whereby the M_(PAT) agent is acting against theS_(AT) or S_(T) sequence(s) and/or the corresponding transcript(s),which is (are) present in native or mutant form and/or complete or afragment.

In the framework of the present invention, an agent for treating tumordiseases is moreover suggested that contains at least one M_(PAT) agentselected from the group that includes polyclonal antibodies, monoclonalantibodies, and fragments and derivatives thereof, and whereby theM_(PAT) agent is acting against one or more translation products of oneor more of the S_(AT) or S_(T) sequences and/or of the correspondingtranscript(s), which is (are) present in native or mutant form and/orcomplete or a fragment and whereby the said translation product or saidtranslation products is (are) present in native or mutant form and/orcomplete or as a fragment and/or glycosylated or partially glycosylatedor not glycosylated and/or phosphorylated or not phosphorylated.

The invention suggests a further agent for treating tumor diseases thatis characterized by at least one translation product of one or moreS_(AT) or S_(T) sequences and/or of the corresponding transcript(s),which is (are) present in native or mutant form and/or complete or as afragment and whereby the said translation product(s) is (are) present innative or mutant form and/or complete or as a fragment and/orglycosylated or partially glycosylated or not glycosylated and/orphosphorylated or not phosphorylated and/or chemically modified or notchemically modified.

Finally the invention provides another agent for treating tumor diseasesthat includes at least one M_(JAT) agent that is an expression inhibitorthat has greater specificity for one or more of the S_(AT) or S_(T)sequences than for other tissues of the corresponding genetic system.

Furthermore the invention provides an agent for treating tumor diseasesthat includes at least one M_(JAT) agent that is an expression inhibitorspecific for at least one of the S_(AT) or S_(T) sequences.

In a preferred form of embodiment it is provided that the tumor to betreated expresses a gene selected from the group that includes MAGgenes, high mobility group protein genes, HMGI-C genes, HMGI-Y genes,and their derivatives.

It can furthermore be provided that one of the agents of the inventionis used to produce a drug for treating tumor diseases.

In a preferred form of embodiment it is provided that the drug is usedfor treating types of tumors that express a gene selected from the groupthat includes MAG genes, high mobility group protein genes, HMGI-Cgenes, HMGI-Y genes, and their derivatives.

In a further form of embodiment it can be provided that at least oneagent of the invention is used for treating types of tumor that expressa gene selected from the group that includes MAG genes, high mobilitygroup protein genes, HMGI-C genes, HMGI-Y genes, and their derivatives.

A DNA sequence according to the invention, which is characterized by asequence as shown in SEQ ID NOs: 1 to 19, is advantageous for developingnovel agents based on this sequence and its corresponding transcriptsand translation products, whereby the nucleic acids must be confirmed tobe molecules carrying information in their structures. Such agents canbe drug products, as well as agents used in diagnostics, but are notlimited to these. These agents can also be used advantageously invarious processes and also for the therapy of various illnesses or forproducing appropriate drugs for treating these illnesses. Thus with thedescription of the sequences of the invention, a versatile agent is madeavailable. It must be noted thereby that the advantages resulting fromthe sequences of the invention are not limited to an exactcharacterization of a specific site of action, which can therefore beaffected by the use of suitable agents, including those of theinvention, but the corresponding sequences themselves serve to causeeffects based on the presence of the sequences of the invention orsequences derived therefrom and/or their transcripts and/or theirtranslation products. These sequences can also be affectedadvantageously if they are biologically active as such in an organism,whether as a result of basic biological processes or as a result of theintroduction of these sequences by means of a technical measure, or inan in vitro system.

These general advantages are also furnished if parts of the sequencesshown in SEQ ID NOs: 1 to 19 are a part of the DNA sequence of theHMGI-C gene.

The term “genes” in connection with this Application is intended toinclude the sequence of the exons and introns and also the correspondingcDNA of the respective gene.

Compared with the sequences shown in SEQ ID NOs: 1 to 19, mutations ofthe DNA sequence of the invention offer a further advantage in that theyenable a sequence-specific agent, e.g. in the form of an antisense DNAacting against the sequences of the invention, to be distinguished fromother sites of action if necessary, and thus the stringency occurringwhen nonmutant sequences are used would not guarantee the requiredspecificity of interaction between the respective complementary strands.

Mutation in the sense of the present invention also includes afragmentation of the sequences, whereby fragmentation includesshortening of the sequences at the 5′-end and/or at the 3′-end up to anoligomer, as well as loss of a sequence(s) of at least one nucleotidearranged within the sequence. Moreover the term “fragmented sequence orgene” herein is intended to include a sequence/gene that has one or moreintrons that can be respectively deleted partially or completely.

Furthermore, such mutant sequences allow translation products to beobtained whose biological activity is essentially identical to that ofthe translation products of native sequences. On the level of the aminoacid sequence of the translation products, such mutations can manifestthemselves in a variety of ways, including insertions, deletions, orsilent mutations, among others. On the DNA level, such mutations allowthe sequence to be matched to the use of certain tRNA anticodons andthus make it possible to match the translation rate of the correspondingsequences to the respective requirements or the respective host system.

On the other hand, applications are conceivable in which essentially thesame sequence as the DNA sequence shown in SEQ ID NOs: 1 to 19 isadvantageous and e.g. delivers the necessary stringency. A modifiedversion of the DNA sequences of the invention also offers thepossibility of including suitable signals recognized by the biologicalbackground. The presence of such signals can lead to a changedtranscription and/or translation rate, e.g. as a result of an increasedhalf-life of the transcripts, but is not limited to this.

The aforementioned advantages can also exist when nucleic acid sequencesare used that are only functionally the same. It must be taken intoconsideration thereby that the term “functionally the same nucleicacids” takes into account the functional principle on which the HMGI-Cgene, but also in general the MAG genes or the high mobility groupprotein genes, is based.

Without prejudice, there exists in the literature the perception thatthe corresponding gene products essentially consist of a DNA-bindingportion and a protein-binding portion. As a result, this term“functionally the same nucleic acid sequence” is also intended toinclude those sequences that code for translation products with asimilar function to the translation products of the sequences of theinvention or of the MAG genes or of the high mobility group proteingenes. The advantageous effects described above must also be taken intoaccount for such translation products. The term is also intended toinclude those nucleic acid sequences that lead to a translation productthat is functionally the same, i.e. those that lead to a functionallystill active translation product in the above sense as a result of thedegeneration of the genetic code. The fact that the sequences of theinvention have a (nucleic acid) sequence that codes for a DNA-bindingportion of the corresponding translation product(s), ensures that thesequences of the invention yield a translation product that is capableof binding to DNA. Vice versa, the nucleic acid sequence as such gives aprecisely defined target for agents in which the required sequencespecificity is inherent in their molecular structure, such as e.g.antisense DNA or antibodies acting against the DNA-binding portion ofthe sequence and/or of the corresponding translation products.

Because sequences of the invention sometimes lack a sequence that codesfor the protein-binding moiety of the translation product(s)corresponding to the DNA sequences of the invention, there exists thepossibility of influencing in a desired manner the effect on thechromatin structure that would otherwise be mediated via theprotein-binding portion.

If on the other hand one or more S_(r) sequences is (are) present thatreplace(s) or complete(s) the sequence(s) that code(s) for theprotein-binding portion of the translation product(s) corresponding tothe sequences of the invention, this opens up the advantageouspossibility of a specific interaction with cellular (protein)components. As a result, other cellular factors can interact with theadditional or new portions of the translation product. Vice versa, atthe DNA level another region can thus be introduced that allows aresponse to the sequences of the invention.

Depending on the respective question under consideration, the sequenceS_(r), which is selected from the group that includes other sequences ofthe human genome, sequences of other (donor) organisms and artificialsequences and combinations thereof, also offers many possibilities forinfluencing cellular events.

The fact that the sequences shown in SEQ ID NOs: 1 to 19 are aberranttranscripts of the HMGI-C gene, makes it possible to distinguish betweenaberrant transcripts on the one hand, and non-aberrant transcripts onthe other hand, and also between the respective translation products.For those skilled in the art, this results in a wealth of advantages inboth the therapeutic and diagnostic fields.

Thus it is e.g. conceivable that the translation products of theaberrant transcripts stimulate or interrupt certain reaction chains inthe cellular events, for example by acting as competitive inhibitors.

With an expression vector of the type according to the invention, whichincludes at least one transcription promoter followed downstream by atleast one DNA sequence of the invention, there exists the possibility ofobtaining corresponding transcripts and translation products of the DNAsequences of the invention in a simple and rapid manner.

Using a further form of embodiment of the expression vector, there isalso the possibility of transforming or transfecting various hostsystems. Depending on the respective host system used, various promoterscan be provided, both eukaryotic and prokaryotic, as well as optionallyenhancer elements and/or suitable termination elements, as aresufficiently well-known in the state of the art.

Whether a prokaryotic or a eukaryotic cell is used as the host celldepends on the purpose for which the expression vector is being used.Owing to their nutrient requirements and comparatively greater ease ofcultivation, prokaryotic cells are to be preferred when the inherentdisadvantages of host systems of this type, such as e.g. lack ofglycosylation or possibly the formation of inclusion bodies, are notimportant for the purpose of the cultivation.

On the other hand eukaryotic cells, especially yeast cells and mammaliancells, offer an advantage, e.g. when post-translational modificationsare important for the further intended use.

Advantages are also gained from a protein or peptide that is atranslation products [sic] of one or more S_(AT) sequences and/or of thecorresponding transcript(s) that is (are) present in native or mutantform and/or complete or as a fragment, and whereby the said translationproduct(s) is (are) present in native or mutant form and/or complete oras a fragment and/or glycosylated, partially glycosylated, or notglycosylated and/or phosphorylated or not phosphorylated and/orchemically modified or not chemically modified. Thus there exists thepossibility of preparing effector molecules coded by the S_(T) and/orS_(AT) sequences, without changing the genetic background of the systemunder observation. In addition to direct substitution or completion ofthe cellular level with respect to the translation product(s) TP, e.g.in the form of “flooding,” the possibility is also offered ofinfluencing cellular events by using derivatives present in native ormutant form and/or complete or as a fragment, including the variouspossible glycosylation forms and the physiologically particularlyimportant phosphorylation forms and other modified forms, whereby thesaid molecules can assist the effect of the native translation productif necessary, or else e.g. can also initiate this or can respond to thecorresponding attachment sites of cellular mechanisms in the sense of acompetitive inhibition.

The use of at least one sequence of the invention and/or of an MAG geneor at least a high mobility group protein gene and particularly the useof the HMGI-C gene or the HMGI-Y gene to influence vessel development isadvantageous in that it gives a specific site of action as well asspecificity of the agent to be used in principle to influence vesseldevelopment. This ensures that the expression of the corresponding genesor sequences is influenced by a suitable agent, which can include thecorresponding genes or sequences themselves. Based on this very directmechanism of action, all those disadvantages that occur with indirectmechanisms of action are avoided to a very great extent. This leads toless disturbance of the cellular processes in the sense of a nonspecificdisturbance and thus in the end also to reduced secondary effects on thesystemic level.

The explanations given above in connection with the advantageous effectsof mutations and other forms of the S_(AT) sequences of the inventionalso apply to the S_(T) sequences of course, and are included herein forreference.

The advantageous effects are also furnished when the S_(T) and/or S_(AT)sequences are present as a double strand and/or a coding and/ornoncoding single strand and/or cDNA. It lies within the framework of thepresent invention if the said sequences are present as DNA or as RNA.The use of such constructs according to the invention enables somaticand/or transitional gene therapy for influencing vessel development.

Furthermore it is advantageous if the corresponding sequences are alsopresent as a single strand, whether coding or noncoding, whereby agentscan then be used that act specifically on the single strand, in order toensure that vessel development is influenced. It is possible for thoseskilled in the art to utilize the said sequences in both their native ormutant form and/or their fragmented form, without having to forego theadvantage of the directly mediated action. Here too, the previousexplanation concerning mutation and fragmentation applies.

Vessel development can also be influenced advantageously if the S_(T)and S_(G) sequences have at least one eukaryotic promoter and/or atleast one enhancer element and/or at least one transcription terminationelement and/or at least one resistance gene and/or at least one othermarker gene. The transcription and/or translation can be influenced bythese elements in a way that is more advantageous for influencing vesseldevelopment. Thus a suitable eukaryotic promoter can be controlled, e.g.via the presence of specific factors and thus a predetermined expressioncan be induced by endogenous and/or exogenous factors. Resistance geneswould allow further distinguishing of the cell populations to beinfluenced and could also be used as selection markers. A marker genewould be advantageous in this connection in so far as an indication ofthe processes proceeding at the molecular or molecular-genetic levelcould be ensured thereby.

Because the S_(T) and/or S_(AT) sequences are present as clones in ahost system, there exists the possibility of achieving vesseldevelopment both in vivo and in vitro via the effects of the level ofexpression caused by the natural presence of the S_(T) and/or S_(AT)sequences. This can lead, for example, to particularly rapid vesselgrowth.

The fact that at least one copy, i.e. an S_(T) and/or S_(AT) sequence ofthe invention, is present in the respective biological system, makes itpossible to achieve further advantageous effects in the sense of theabove explanations, via gene dosage effects.

An agent of the invention for influencing vessel development selectedfrom the group that includes sense DNA, sense RNA, sense cDNA, antisenseDNA, antisense RNA, and antisense cDNA, and combinations thereof, as asingle strand and/or a double strand, whereby this agent is (are) [sic]present in native or mutant form and/or complete or as a fragment and/orchemically modified or not chemically modified, is particularlyadvantageous.

If the sequence of the agent(s) corresponds to an S_(T) or S_(AT)sequence(s) or to the corresponding transcript(s), which is (are)present in native or mutant form and/or complete or as a fragment, it ispossible to exert an influence via a corresponding interaction betweenthe respective nucleic acids [text missing in original] the expression,i.e. the transcription and/or translation on the influencing of vesseldevelopment advantageously. Thus, it is e.g. conceivable to raise thelevel of expression of the corresponding sequences by using a suitablesense DNA or sense RNA. Vice versa, it is conceivable, e.g. in the caseof reducing tumor angiogenesis, to use corresponding antisenseDNA/antisense RNA and thus to reduce the expression. As a result of thereduced expression of the S_(T) and/or S_(AT) sequences, tumorangiogenesis is reduced, which leads to a reduction in the volume of thetumor until it disappears. Corresponding mechanisms are also obtainedwhen cDNA or antisense cDNA are used. The advantageous effect can alsobe observed when the corresponding agent is present in non-native form,i.e. mutant and/or fragmented. Such mutations are advantageous in so faras the interaction of the sequence-specific agents with the S_(T) and/orS_(AT) sequences and/or cellular factors can be distinguished againstthe genetic background. Vice versa, a possibly advantageous response oforiginal target sequences is possible with a sequence that is largelynative. The corresponding sequences of the agents used do notnecessarily have to be present in complete form, i.e. in completelength; favorable effects can also be achieved when they are present asa fragment, as defined above.

It is also conceivable for the agent of the invention to be introducedinto the cell or be present there and itself serve as a matrix, and forit to have biological effects. Such effects can be caused by DNA and/orRNA and/or corresponding translation products. Thus the possibility ofsomatic gene therapy and/or transitional gene therapy is opened up bythe agents of the invention.

Although the use of both DNA and RNA is possible in principle within theframework of the agents of the invention, owing to the reduced stabilityof RNA in biological systems, the use of DNA may be appropriate when alonger-term effect is desired, and vice versa the use of RNA may beappropriate when only a short-term influence on the correspondingsequences is desired.

Chemical modification of the agents of the invention may be advantageousamong other things in so far as e.g. the biological half-life of theagent can be influenced thereby and thus the duration of the action ofthe agent of the invention can be influenced precisely.

There are quite particular advantages when the corresponding agent isacting against the S_(T) and/or S_(AT) transcripts. Thus theaccessibility of the transcripts relative to the sequences typicallypresent as a double strand can be important for the effectiveness of theinhibition, but also for the effectiveness of the stimulation. Inaddition to the native form, the mutant form of the transcript alsooffers the possibility of a further influencing of the specificity ofthe interaction, whereby the corresponding transcripts can optionally bepresent complete or as a fragment, whereby the various splice forms areto be understood as a fragment in addition to the forms defined above.

With an agent of the invention for influencing vessel developmentselected from the group that includes polyclonal antibodies, monoclonalantibodies, and fragments and derivatives of the same, a specific toolis made available for advantageous use. The specificity of said agent isacting against the S_(T) and/or S_(AT) sequences and/or thecorresponding transcript(s), which is (are) present in native or mutantform and/or complete or as a fragment. Thus the aforementionedspecificity of the agent causes a highly specific interaction with saidsequences. In addition to the epitopes established by the nativesequences, including those yielded by the respective transcriptionproducts, the mutant transcription products of the optionally mutantsequences are also tissue- and organ-specific compared with theremaining cellular antigenic background, or that of other cells, so thatthe target cell specificity of optionally systemically applied agentsrequired for influencing vessel development—associated with the fewestpossible side effects—is ensured. The same also applies to the presenceof fragments of the transcription products.

In addition to the use of polyclonal and monoclonal antibodies, the useof fragments and derivatives thereof can also be particularlyadvantageous in the sense of the present invention. Fragments includeall those forms of molecules derived from antibodies that continue toallow more or less specific binding to an antigen or epitope.Derivatives are understood to mean antibodies or fragments derived fromthe original structure of the antibodies. These include, among others,antibodies comprising only one protein chain, as well as markedantibodies. Markings include all those described in the literature andinclude among others marking with enzymes, luminescence,complex-formers, biotin and biotin derivatives, digoxigenin, andradioactive markers.

It is furthermore provided that the antibodies, fragments, andderivatives of these are modified so that uptake into the cell ispossible utilizing biological and/or chemical and/or physicalmechanisms. Such a modification can consist for example in that themolecule has at its disposal an additional structure (e.g. acorresponding domain or attached compound) that enablesreceptor-mediated or other, possibly nonspecific, uptake.

What has been explained above with respect to the specificity of thesaid agent opposite to S_(T) and/or S_(AT) sequences or thecorresponding transcripts also applies to their translation products.Here too, in addition to the [text missing in original] by the nativeform of the translation products of the sequences or their transcripts,those translation products are particularly important that aretranslated from mutant sequences. In addition to the numerous epitopesof the native translation products present, the aberrant translationproducts are of particular interest for a selective response by definedcell populations, whereby in addition to the disappearance of epitopespreviously present, the new appearance of epitopes is also ofimportance. Such epitopes can in principle be caused both by the primarysequence and also by the secondary, tertiary, or quaternary structure,and can also affect the glycosylation and phosphorylation sites.

The specificity of an agent for influencing vessel development can alsobe influenced by an agent that is itself selected from the group,including polyclonal antibodies, monoclonal antibodies, and fragmentsand derivatives of these, in that this agent is acting against theantibodies or fragments or derivatives, which for their part are actingagainst the S_(T) and/or S_(AT) sequences and/or the correspondingtranscript(s) in their various forms, as defined above, or opposite tothe corresponding translation product(s) in their various forms.

An advantageous influencing of vessel development is also allowed by anagent of the invention for influencing vessel development that [wordmissing in original] at least one translation products [sic] of one ormore S_(T) and/or S_(AT) sequences and/or of the correspondingtranscript(s) that is (are) present in native or mutant form and/orcomplete or as a fragment, and whereby the said translation product(s)is (are) present in native or mutant form and/or complete or as afragment and/or glycosylated, partially glycosylated, or notglycosylated and/or phosphorylated or not phosphorylated and/orchemically modified or not chemically modified.

The said advantages of a protein or peptide that is a translationproduct of one or more S[sub]AT sequences and/or of the correspondingtranscript(s), which is present in native or mutant form and/or completeor as a fragment, also apply of course to the agent of the invention andare herewith included for reference.

Other advantages result from the use of at least one expressioninhibitor and/or at least one expression-stimulating agent in theframework of an agent for influencing vessel development. Theaforementioned M_(MAKS) and M_(MAKP) agents of the invention can alsorepresent such expression inhibitors or expression-stimulating agents.Expression inhibitors and expression-stimulating agents different fromthese are also included, however. It is within the meaning of thisinvention that the genetic background is modulated relative to theexpression of S_(T) and/or S_(AT) sequences by corresponding inhibitorsor stimulating agents. The desired influencing of vessel development canresult from this relative relationship of the expression of the geneticbackground on the one hand and of the S_(T) and/or S_(AT) sequences onthe other hand. It is also entirely possible to use said M_(MAKS) andM_(MAKP) agents in addition to the—nonspecific, since they influence thetotal genetic background of the cellular system—inhibitors and/orstimulating agents.

The selectivity of the influencing of vessel development can beincreased in an advantageous manner with an increased specificity of theexpression inhibitor or the expression-stimulating agent for one or moreof the S_(T) and/or S_(AT) sequences, compared with other genes of thegenetic system concerned.

The said advantages concerning the influencing of vessel developmentalso extend to angiogenesis, whereby this can if necessary be reducedand/or interrupted in an advantageous manner. Vice versa, stimulation ofangiogenesis is also possible and can be carried out advantageouslyusing the S_(T) and/or S_(AT) sequences in the broadest sense, includingthe corresponding translation products and the agents of the invention.

The agent of the invention is of central importance for influencingvessel development when this relates to tumor angiogenesis. As alreadyexplained, the presence of a vascular system is essential for the growthof a tumor. With the sequences and agents of the invention or the use ofthe invention of the S_(T) sequences in the broadest sense and includingthe translation products and the agents derived therefrom, it is nowpossible to control tumor angiogenesis and thus a novel method is setforth for the treatment of various tumors. Thus comparativelynonspecific therapies such as chemo- and radiation therapy with theirwidely known side effects become obsolete, and instead a highly specificform of therapy is made possible. A further impairment of systemicangiogenesis can also be avoided by suitable measures, such as e.g.administration of the agent explicitly at the site of the tumorangiogenesis.

Said specificity is based among other things on the fact that strongerexpression of HMGI-C has not been found hitherto in any tissue of theadult organism, with the exception of the endometrium, so that in factthe development of blood vessels in the environment of the tumor can beinterrupted selectively.

The explanations given in connection with angiogenesis also apply whenthe agents or their use relate to influencing vessel development in thesense of vascularization.

Just as in other diseases, processes of (neo-)angiogenesis,(neo-)vascularization, and disturbances of vascularization also play alarge part in vision impairments such as e.g. in diabetes mellitus. Thusan advantageous specific treatment is possible here too, using theagents or sequences of the invention, as is surmounting the initiallyexplained disadvantages of existing therapies. The preventive aspect ofsuch a treatment is of considerable importance when the agents orsequences of the invention are used according to the invention, so thatfurther impairment of the health and well-being of the patient by avision impairment is avoided.

The use according to the invention of the agents of the invention forinfluencing vessel development can be used advantageously in improvingthe blood supply of infarct-damaged heart muscle tissue.(Neo-)angiogenesis and (neo-)vascularization enable the heart muscletissue to be better supplied with vessels thereby. In addition toachieving a fundamentally improved state of health of infarct patients,either bypass operations can be omitted completely or the healingprocess can be successfully reinforced. Moreover the use according tothe invention relates to improved blood supply to the heart muscletissue in general and to that of high-risk patients specifically.

The advantages with respect to influencing vessel development extend toboth the human and animal organism, whereby a therapeutic and/ordiagnostic use is advantageous in humans and/or animals.

In addition to the direct benefit that a human experiences by theinfluencing of vessel development, whether for regeneration purposes orfor the treatment of tumor diseases or effects of diabetes mellitus(impairment of vision), the benefit can also be of an indirect nature,e.g. when appropriate vessel material is produced for transplantationpurposes, under the influence of the sequences and/or agents of theinvention or uses in animals.

Use in the sense of veterinary medical use is also included, of course.

In addition to this very broad therapeutic use, an advantageousdiagnostic use is also possible in principle in both humans and animals.It is particularly advantageous thereby to use the M_(MAKS) and M_(MAKP)agents, above all when they carry markers that can be detected by meansof non-invasive test methods. Thus, for example, it can be checkedwhether a therapeutic measure has the desired success at the geneticlevel. Influencing vessel development according to the invention is alsoadvantageous when an agent of the invention and/or one of the S_(T)and/or S_(AT) sequences or their uses is (are) used in vitro. Thisincludes use in cell, tissue, and organ cultures, among others.

Finally, the agent of the invention or its use can also be used toproduce a drug for therapeutic and/or diagnostic use, so that a drug isavailable that is clearly superior to agents of the state of the artused for the purpose of influencing vessel development or for thepurpose of treatment of diabetes mellitus and tumor diseases, as far asside effects associated with these are concerned.

The aforementioned advantages also apply of course to the kit of theinvention in its various forms of embodiment and are included herein forreference. The same applies to the advantages resulting from theindividual components of the kit.

The advantages of a kit are generally considered to be in that, amongother things, the respective agent is ready prepared in the optimalmanner for its use. This also includes a suitable spatial arrangement.Advantageous effects can result thereby precisely from the combinationof the various agents.

In addition to its therapeutic use for influencing vessel development,including reduction of tumor angiogenesis for treating effects ofdiabetes mellitus and for improving vessel provision of infarct-damagedheart muscle tissue, the kit of the invention can also be used fordiagnostic and test purposes; e.g. information can be gainedadvantageously as to how far certain therapeutic measures arecharacterized by success or whether certain substances produce theeffects ascribed to them.

The explanations given in connection with the use of the S_(T) and/orS_(AT) sequences of the invention in the broadest sense, including thecorresponding transcripts and translation products, as well as inconnection with the agents of the invention for influencing vesseldevelopment, of course apply also to their use for treatingendometriosis and to corresponding agents and kits of the invention fortreating endometriosis and are included herein for reference.

Without prejudice, it is assumed that the structuring of the endometriumtakes place under the influence of the expression of the HMGI-C gene,even when endometriosis is present, as a result of which influencing theexpression of this gene or functionally similar genes by using the saidsequences or agents and kits leads to a specific treatment forendometriosis that is virtually free of side effects.

The explanations given in connection with the use of the S_(T) and/orS_(AT) sequences of the invention in the broadest sense, including thecorresponding transcripts and translation products, as well as inconnection with the agents of the invention for influencing vesseldevelopment, of course apply also to their use for contraception and tocorresponding agents and kits of the invention and are included hereinfor reference.

Here too the invention is based on the surprising finding that theHMGI-C gene participates in the structuring of the endometrium. When thesequences or agents of the invention are used, contraception orpregnancy is achieved by specifically influencing the endometriumreceiving the fertilized ovum, for example in the sense of suppressingits structuring. Since the HMGI-C gene is expressed almost exclusivelyin the endometrium in the healthy adult human organism, this ensuresthat even when an appropriate agent is applied systemically, only thedesired target site, i.e. the endometrium, is exposed to the influenceof the corresponding agents of the invention and thus the side effectsobserved when hormonal agents are administered for contraception arevirtually absent.

The uses according to the invention or agents and methods forcontraception provide for local contraception as well as oralcontraception. In addition to the significant advantage of decidedlysimple and reliable oral administration in the framework of oralcontraception, local contraception also offers advantages. Thus theformulation of the appropriate preparations can be simple, sincegastrointestinal passage is not necessary. Instead, it can be ensured bymeans of e.g. aerosols that the agents of the invention reach their siteof action, i.e. the endometrium, directly.

Further advantages resulting from the individual forms of embodiment ofthe use of the invention, like those resulting from the agents of theinvention for contraception and the methods of the invention forcontraception, have of course already been stated in connection with theinfluencing of vessel development and are included herein for reference.

As far as advantageous effects are concerned, it can also be stated thatby periodic administration of the agent of the invention or by means ofthe processes of the invention, a cyclicity becomes possible withrespect to the structuring of the endometrium that may be useful fromthe point of view of basic medical or biological considerations andrepresents a therapeutic use of the agents of the invention, for examplein cases of menstrual problems.

An advantage of the process of the invention that should be particularlyemphasized is that the agents of the invention can be administered afterconception. Without prejudice as to the mechanism of action, it can bestated that according to our present understanding, the structuring ofthe endometrium can be influenced before, during, and after nidation byinfluencing the expression of the HMGI-C gene or analogous genes, sothat the endometrium degenerates and the pregnancy is interrupted.

The explanations given in connection with the use of the sequences ofthe invention and S_(T) sequences in the broadest sense, including thecorresponding transcripts and translation products, as well as inconnection with the agents, kits, and optionally processes of theinvention for influencing vessel development and for contraception, ofcourse apply to their use for tissue regeneration and to correspondingagents, kits, and methods of the invention, and are included herein forreference.

Tissue regeneration is understood herein to mean both regeneration oftissue with recourse to exactly the type of tissue to be regenerated, inthe sense of an increase in the mass of the tissue, as well as theproduction of new tissue starting from a different type of tissue orcell than that to be produced.

Furthermore the uses, agents, kits, and processes of the invention fortissue regeneration allow the regeneration of tissue that hitherto couldnot be regenerated or only with difficulty, or makes correspondingregeneration processes safer overall both for the personnel entrustedwith the task of tissue regeneration and for the final recipient of thetissue regenerated in this manner; through the use of the invention andthe kit of the invention and the process of the invention, however,defined conditions are created that allow a specific intervention in thesequence of events of tissue regeneration, while avoiding theinvolvement of material from biological sources that pose a risk, atleast latent, in the form of possible viral (hepatitis C, HIV) andbacterial contamination, as well as factors not toleratedimmunologically (anaphylactic shock).

The use of at least one of the agents of the invention in vivo isassociated with considerable advantages for a number of reasons. Thusfor example no collection of material is required from any tissue ororganism whatsoever. Thus rejection reactions resulting from tissueincompatibility and problems that might result from the use of materialfrom biological sources do not occur.

Vice versa, the use of at least one of the agents of the invention invitro can likewise be advantageous, namely when a corresponding use isnot possible under the conditions currently prevailing in the organism.This may be the case e.g. when no tissue is available in principle thatis suitable to serve as starting material for the regeneration processof the invention. The use in or on cultures selected from the group thatincludes cell cultures, tissue cultures, organ cultures, andcombinations thereof, facilitates controlled tissue regeneration to anot inconsiderable extent, while the uses of the invention or agents andprocesses used for this purpose can be used and carried out underdefined conditions. Moreover there exists the possibility in such invitro systems of producing corresponding material beyond the respectivecurrent need and thus of being in a position to satisfy an unforeseenneed.

In connection with this Application, a therapeutic treatment is alsointended to include such a treatment for cosmetic purposes.

It is moreover held that the use of an agent of the invention is quiteparticularly advantageous in the process of the invention.

For the process of tissue regeneration, a variant can also beadvantageous from the point of view of cost-effectiveness of the processor safety, in which the prepared or cultivated target cells alreadyexpress at least one of the S_(T) and/or S_(AT) sequences, whereby theprocess step of the invention would omit the introduction of at leastone of said sequences. The subsequent steps of the process remainunchanged.

Depending on the tissue to be regenerated, various processes can beselected to introduce the S_(T) and/or S_(AT) sequences. Those skilledin the art can ascertain the optimal transformation- or tranfectionprotocol in each case by appropriate routine tests.

Target cells originating from a human are quite particularlyadvantageous. The human concerned can be the person who is to receivethe tissue regenerated according to the invention, or else anotherperson who is a suitable donor. In principle, target cells from a deadperson can also be used. The latter may be the case, e.g. if no suitableliving donor is available, or if a suitable donor is already dead andhis tissue, for example because of age, is no longer suitable for directtransplantation purposes.

It can also be advantageous, however, if target cells originate from ananimal organism other than a human. Thus, e.g., the use of target cellsthat originate for example from a transgenic animal may make sense undercertain conditions, particularly if the transgenic animal yields targetcells that are histocompatible with those of the recipient organism orhave other advantageous properties.

The use of target cells that represent a different type of cell from thecell types contained in the tissue to be regenerated is advantageouswhen target cells taken from the tissue to be regenerated are notsuitable for regeneration purposes. Using the process of the invention,corresponding agents, and kits, such target cells can be caused toregenerate in the sense of a proliferation and differentiation.

Vice versa, the use of target cells that belong to the same cell type asthat contained in the tissue to be regenerated can increase the successof the process, above all when the tissue to be regenerated is stillsufficiently intact, but the extent of the tissue still present is notenough to fulfill the respective biological function to its full extent.

The (de-)differentiation of the target cells under the influence of atleast one of the S_(T) and/or S_(AT) sequences of the invention in thebroadest sense, including of the corresponding transcripts andtranslation products, as well as agents of the invention acting againstthese, to produce pluripotent stem cells, allows cells to be changedinto a condition that allows development of the respective cell intoeach mesenchymal cell type and thus allows the regeneration of almostany desired mesenchymal tissue. This also includes a case in which thedirection in which the regeneration of the invention finally proceeds,is determined by the influence of additional factors, if necessary ofthe cellular environment in which the cell is situated or into which thecell is introduced.

Advantageous effects occur when target cells of the process of theinvention are co-cultivated with other cells and/or cell types. Asalready indicated in the above section, co-cultivation can have adeterminative influence on the direction of the (re-)differentiation ofthe target cells in the sense of a tissue regeneration. Withoutprejudice, it can be assumed that influences apparently emanate from thecells used for the co-cultivation that influence the differentiationstate of the target cells. Such an influence can be mediated by more orless soluble factors, but also cellularly, with the latter alsoincluding interactions of cell membrane structures or components in thebroader sense as well as other physical or chemical phenomena such ase.g. membrane potentials.

Depending on the type of tissue to be regenerated, as well as on thesources available in principle, the material collected from an organismcan be selected from the group that includes cell-containing biologicalfluids, cells, single cells, tissue, and organs. With the collection ofcell-containing biological fluids or single cells, it is ensured thatfurther steps to recover single cells from tissues or organs are avoidedto a great extent. This ensures that cells are utilized for regenerationpurposes that actually appear to be best suited for the respective case.It can also be advantageous, however, to collect tissue or even completeorgans. Thus it is conceivable that with the collection of tissue ororgans, several cell types are available whose suitability can be testedduring a routine test processing. Moreover when tissues or organs arecollected, an advantage can result in that otherwise the collection ofsuitable cell material would be impossible.

After introduction of at least one of the S_(T) and/or S_(AT) sequencesof the invention, the introduction of target cells into an animalorganism offers advantages in that the respective animal organism,including the human, thus contains biologically active tissue in orderto eliminate defects or deficiencies relating to this. The target cellscan be introduced thereby when the target cells are either in the formof single cells, or, after cultivation, are already in the form of cellaggregates, tissue, or the like. Finally it is also conceivable inprinciple for the target cells to be introduced into an animal organismin order to develop there further under the influence of the biologicalsystem. Later collection of the target cells further modified and/orincreased and/or differentiated in the biological system, i.e. theanimal organism, is likewise to be included thereby.

After introduction of at least one of the S_(T) and/or S_(AT) sequencesof the invention into the target cells, it can be advantageous to inducetheir expression in the target cells before the target cells areintroduced into an animal organism. The advantage is that thus thepossible influence of the biological system on the differentiation islimited. This can be particularly advantageous when differentiation ofthe target cells in the desired direction would not be guaranteed in acellular environment owing to the differentiation factors or signalsthere.

Vice versa, it is also advantageous, after introduction of at least oneof the sequences of the invention or S_(T) sequences, to induce theirexpression in the target cells after the target cells have beenintroduced into an animal organism. This subsequent induction can beadvantageous if the proliferation and/or differentiation of the targetcells is only to take place under the influence of the target region orthe target tissue with its specific differentiation signals and factors,in order to exclude premature differentiation in a direction other thanthe desired one.

Of course, the said advantages also result with respect to whether thetarget cells introduced into an animal organism are in a differentiatedand/or differentiation-competent state.

If the animal organism into which the target cells are introduced is ahuman organism, particular advantages result therefrom, among otherswith respect to the treatment of degenerative diseases, such as e.g.arthritic diseases or muscular dystrophy. Similar to the advantagesdiscussed in connection with the recovery of suitable target cells,these also result from the fact that the target cells are introducedinto an organism that is identical with the organism from which thetarget cells were collected.

Vice versa, it can also be advisable for the organism into which thetarget cells are introduced to be different from the organism from whichthe target cells originate, e.g. when the organism into which the targetcells are introduced no longer has any of its own starting materialavailable.

Quite particular advantages result in the processes of the inventionwhen at least one of the S_(AT) sequences of the invention or the S_(T)sequence is introduced into the tissue in the organism that is to beregenerated and/or the corresponding cells. Such a measure ensures thatno surgical operations are required, either for collection orreintroduction of corresponding material, which is of central importancewhen the regions from which the material is collected or into which thematerial is introduced are only accessible by invasive means. Moreoverthe work required is reduced, as is the risk that the tissue to beregenerated is contaminated or else that a non-optimal regenerativedevelopment occurs under the conditions of in vitro cultivation.

Introduction of the constructs concerned as such into the tissue to beregenerated and/or the corresponding cells using gene therapy processespresents a quite particularly advantageous possibility, with particularadvantages resulting from the use of suitable viral systems. Usingroutine tests for the application concerned, those skilled in the artcan ascertain the process required for introduction of the sequences.

Finally, other advantages also result from the fact that expression ofthe introduced sequences of the invention and the S_(T) sequences isinfluenced by at least one M_(MAKS) agent and/or at least one M_(MAKP)agent and/or at least one translation product TP and/or at least oneexpression-stimulating agent ES. Thus there exists the possibility ofcontrolling the extent of the regeneration both with respect to itsspatial pattern and also with respect to its time course.

The uses and agents of the invention for treating tumor diseases aregenerally advantageous in so far as a specific therapy for tumordiseases thus becomes possible, without the occurrence of systemic sideeffects as is the case with other therapies for treating tumor diseasessuch as e.g. chemotherapy or radiation therapy. As already stated, onlya few tissues in the healthy organism express the S_(AT) or S_(T)sequences of the invention, whereas they are expressed strongly in anumber of tumor diseases. As a result the agents, kits, and processes ofthe invention, which are specific for said sequences, allow a specifictherapy for cancer, which moreover is free of side effects as a resultof the mechanism of action on which it is based.

Although not limited to these, quite particular advantages with respectto specificity and reduction of side effects, as well as efficacy of theagent of the invention, result when the tumor to be treated expresses agene selected from the group that includes MAG genes, high mobilitygroup protein genes, HMGI-C proteins, HMGI-Y genes, and theirderivatives. The same applies to the use of at least one of the agentsof the invention for producing a drug for treating tumor diseases.

Further advantages of the various forms of embodiment of the agents ofthe invention and kits that contain these individually or in anycombination for treating tumor diseases, as well as of the uses of theinvention, result of course from the explanations in association withthe uses of the invention of the S_(T) and S_(AT) sequences of theinvention in the broadest sense, including the corresponding transcriptsand translation products, agents and kits and optionally processes forinfluencing vessel development, for contraception, and for tissueregeneration, and are included herewith for reference.

The DNA sequences claimed in the invention are shown as SEQ ID NOs: 1 to19. When the bases given in SEQ ID NOs: 1 to 19 are other than A, C, G,and T, the following nomenclature applies:

R can be A or G, Y can be C or T, K can be G or T, M can be A or C, Scan be G or C, and W can be A or T.

For further illustration of the invention, eight Examples are also givenbelow, chosen at random from the wealth of material available.

The techniques used in the following Examples are summarized below. Whenchanges are required for the individual Example, they are stated at theappropriate points.

Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)

The reverse transcriptase polymerase chain reaction (RT-PCR) includesthe transcription of RNA into cDNA which is then subjected to a regularpolymerase chain reaction using a suitable primer.

In the examples described herein, the RNA was isolated with the TRIzolreagent (Life Technologies, Gaithersburg, U.S.A.). The tissues, healthytissue as well as tumor tissue, were stored under liquid nitrogen forthe time between removal/operation and start of the RNA isolation.

The RNA was transcribed into cDNA using the M-MLV Reverse Transcriptase(Life Technologies, Gaithersburg, U.S.A.), and then used for the RT-PCR.

The RT-PCR was conducted as a so-called nested PCR, that is, as asequence of two polymerase chain reactions with the primers used beingnested into each other. As a special case, in the polymerase chainreaction employed herein the primers were nested on one side only, onthe other side the same primers were used for both polymerase chainreactions. FIG. 1 shows details and the position of the primers withinthe exon of the HMGI-C. The PCR shown in FIG. 1 does not cover shortenedor aberrant transcripts missing the exons 4 and 5. Therefore, inaddition to the PCR with the primers shown above, in some cases a PCRwas used where the primer Revex 4 (see FIG. 1) was replaced by a primerfrom the 3^(rd) exon. The procedure used for the rapid amplification of3′ cDNA ends (3′ RACE PCR, rapid amplification of cDNA ends) was asdescribed by Schoenmakers et al., in Nature Genet 10:436 (1995). Thesequences of all used primers are summarized in Table 1.

TABLE 1 Primers used for the RT-PCR of the HMGI-C,  their sequences (each from 5′ to 3′) and their positions within the gene Primer  name Sequence Position SE1CTTCAGCCCAGGGACAAC Exon 1 (SEQ ID NO: 20) P1 CGCCTCAGAAGAGAGGAC Exon 1(SEQ ID NO: 21) Revex 3 TTCCTAGGCCTGCCTCTT Exon 3 (SEQ ID NO: 22)Revex 4 TCCTCCTGAGCAGGCTTC Exon 4/Exon 5 (SEQ ID NO: 23)

Cytogenetic and Molecular Cytogenetic Procedures

The cytogenetic and molecular cytogenetic procedures (fluorescencein-situ hybridization) were performed according to published standardmethods (Bullerdiek et al., Cytogenet Cell Genet 45:187 (1987); Kievitset al., Cytogenet Cell Genet 53:134 (1990)). The following probes wereused: cRM133, cRM76, cRM99, cRM53 (Schoenmakers et al., Nature Genet10:436 (1995)).

(i) Example 1 Expression of the HMGI-C gene in normal tissue

Different tissue types were investigated with RT-PCR with regard to theexpression of the HMGI-C gene; only tissues of non-tumor source weretested.

The results are summarized in Table 2.

TABLE 2 Tissues tested for expression of the HMGI-C gene, its origin(epithelial/mesenchymal) and extent of the expression of the HMGI-C geneHMGI-C Tissue Origin Gene Myometrium, smooth muscles mesenchymal −Adipose tissue, hypodermis and mesenchymal − Endometriumepithelial/mesenchymal ++ Umbilical cord mesenchymal − Blood vessels(adult) mesenchymal (+) Blood vessels (fetal) mesenchymal ++ Skin(fetal, gestation week 11) epithelial/mesenchymal ++ Cartilagemesenchymal − Cartilage (fetal, gestation week 11) mesenchymal ++ ++:strong expression +: weak expression (+) : very weak expression −: nodetectable expression

From among the tested normal tissues, adult blood vessels showed a veryweak and fetal blood vessels (arteria and vena umbilicalis) asignificantly stronger expression of the HMGI-C gene. Endometrial tissueof the proliferation phase and the fetal tissues also showed a markedexpression. All other tissues showed no expression.

The tests were conducted with the gene of the HMGI-C as a model; basedon the extensive sequence homology and the similar expression patternsin the embryonal and fetal development of the mouse, similar results canbe expected with the HMGI-Y gene.

Example 2 Aberrant Transcripts of the HMGI-C Gene

cDNA was isolated from established cell lines and primary tumor materialfrom human benign mesenchymal tumors (uterus leiomyoma, pulmonaryhamartochondromas, aggressive angiomyxoma) as well as from tumors of thehead salivary glands; it was then amplified by RACE-PCR and sequenced.

The obtained sequences are compared to sequence of the native HMGI-Cgene.

Based on the results of this sequencing, a transcript or its cDNA waslabeled as an aberrant transcript when, as a minimum, the sequence ofthe exons 1-3 (of a total of 5 exons) is present, and the sequence ofexon 3 is followed by a sequence other than that of exon 4 or thesequence of exon 4 is followed by a sequence other than that of exon 5.The sequences fused to the HMGI-C gene were regarded as ectopic whentheir origin from a region of the chromosome 12 other than that of theHMGI-C or from another chromosome could be verified.

The tests performed as described yielded various aberrant transcriptsdetailed in SEQ ID NOs: 1-19. The sequence of the transcripts alwaysstarts with the 1^(st) nucleotide of exon 1 of the HMGI-C gene; theregion of the sequence between the first nucleotide of the first exonand the first nucleotide of the primer was added from a databank. Thesequence contains either the complete sequence to the poly-A tail or apart thereof. In any case, the sequence goes far beyond the 3^(rd) exonor 4^(th) exon and therefore characterizes the aberrant transcript.

Example 3 Rearrangement of the HMGI-C Gene in Hemangiopericytomas

Tumor material from two tumors, fixed in a paraffin matrix, wassubjected to a fluorescence in-situ hybridization. Cosmid clonesobtained from the region of the HMGI-C or the sequences directlyflanking on 3′ and 5′ were used as probes. The tests were performed oninterface nuclei isolated from the tumor material and showed thebreaking points to be within the cosmid covered regions of the tumorstested; this allowed for the conclusion that this is the same type ofmutation as with the other mesenchymal tumors.

Example 4 Differentiation of Cells with Mutant HMGI-C Gene

Cells of tumors with verified rearrangement of the HMGI-C gene (3lipomas, 5 pulmonary hamartomas, 2 uterus leiomyomas) were co-culturedwith normal cartilage cells. The cell culture conditions (Bullerdiek etal., Cytogenet Cell Genet 45:187 (1987)) for the co-cultivation wereadjusted such that in the culture the differentiated status of thecartilage cells was maintained (no addition of fetal calf serum). Thetumor cells originated from primary cultures with additional fetal calfserum. In the cell culture the tumor cells differentiated into cartilagecells, independent of whether they were tumors containing cartilage ornot.

Example 5 Inhibition of Neoaniogenesis and Neovascularisation

Events related to neoangiogenesis, neovascularisation andvascularization defects are important factors not only in thedevelopment of tumors but also in the pathogenesis of many otherdiseases such as diabetes mellitus (Battegay et al., J. Mol. Med. 1995(73), 333-346). The example described herein examined the role of theHMGI-C gene with regard to neoangiogenesis and neovascularisation usingthe techniques described at the beginning and including clonality tests(Noguchi et al., Cancer Res. 52:6594 (1992)). The techniques mentionedat the beginning and the clonality tests showed that the observedvascularization originated from the tumor cells themselves. Because ofthe role of HMGI-C in the proliferation and differentiation ofpericytes, the neovascularisation of myomas, lipomas, leiomyomas andaggressive angiomyxomas originating from the tumor cells, and based onthe data to the gene expression, the (neo)angiogenesis and the(neo)vascularization can be affected as desired by the sequences shownin SEQ ID NOs: 1-19, the sequences S_(T), the claimed means andmaterials, kits and possibly methods, or by their use.

Example 6

Treatment of Endometriosis

The term endometriosis refers to ectopic endometrium that participates“in the normal cyclical and the pathological changes of the endometriumcorporis” (Psychrembel, 1982). The histologic structure conforms to thenormal endometrium in so far as epithelial and mesenchymal componentsare present. It could be shown, using the techniques described at thebeginning, that the organization of the ectopic endometrium is based onthe expression of the HMGI-C gene, similar to physiologically normalendometrium. Therefore, treatment of endometriosis can be based on thesequences shown in SEQ ID NOs: 1-19, the sequences S_(T), the claimedmeans and materials, or their use.

Example 7 Contraception

Using the techniques described at the beginning it could be shown thatthe expression of the HMGI-C gene is involved in the organization of theendometrium. Thus, the sequences shown in SEQ ID NOs: 1-19, thesequences S_(T), the claimed means and materials or their use providemeans and methods for contraception.

Example 8

Chromosomal Breakpoint

Using the techniques described at the beginning, three pulmonaryhamartochondromas were investigated, all of which showed a translocationbetween chromosome 12 and 14 with presence of two normal chromosomes 12and one derivative 14, with the corresponding derivative 12 missing. Thechromosomal breaking point on chromosome 12 was situated 5′ from HMGI-C,the expression of which was also shown in all tumors.

This proves that incorporating one of the sequences S_(T) or S_(AT)leads to a proliferation of normal tissue which can be used for purposesof tissue regeneration or stimulation of angiogenesis orvascularization.

Example 9 Expression of the HMGI-C Gene Upon Cartilage Formation DuringEmbryonal Development of the Mouse

A cDNA fragment of the HMGI-C gene of the mouse (approx. 1.8 kb length,approx. 800 by 5′ UTR to 200 by 3′ UTR) was cloned into an in-vitrotranslation vector. The presence of T7 or Sp6 RNA polymerase promoterswas exploited to synthesize a RNA probe suitable for in-situ RNA-RNAhybridization. This probe was then used for hybridizing in tissue slicesof mouse embryos in different stages of development. The results showthat, among others, a very strong expression of the gene occurs duringcartilage formation from mesenchymal progenitor cells.

This expression is not only detected with mesenchyma of mesodermal butalso of ectodermal origin (head area).

Example 10 Transfection Studies with Expression Constructs and AntisenseConstructs of HMGI-C and its Derivatives

The above-mentioned cDNA fragment of the mouse or a correspondingantisense sequence was cloned into an eukaryotic expression vector. Inthis construct it is controlled by the LTR sequence of Moloney's virusof mouse sarcoma. The construct was then used for thelipofectin-mediated transfection in various primary and establishedcells. Stable transfectants were selected by means of ampicillin. Itcould be shown that upon transfection into primary human fetalfibroblasts the number of cumulative doublings of the transfectantpopulation increased significantly over controls that were onlytransfected with the vector. A reverse effect was observed ontransfection with the antisense construct. The same vector system wasthen used for cloning the described aberrant transcripts of the humanHMGI-C; in this case as well, an increase in the number of cumulativedoublings of the population was also obtained. Depending on the cDNAsequence used this increase was 10-35% higher than with the cDNAsequence of the mouse.

Example 11 DNA-Relaxant Effect of the Proteins Derived from the AberrantTranscripts

Using the DNA sequences SEQ ID NOs: 1-19, consisting of parts of thecDNA sequence of the HMGI-C gene and other DNA sequences mostly appendedto the 3^(rd) exon of this gene, recombinant proteins were synthesizedin the expression vector pET7C and purified.

The proteins purified in this way were then tested for the formation ofthe so-called negative super coils, in the topoisomerase-mediatedrelaxation assay described by Nissen and Reeves (J. Biol. Chem. 270,4355-4360, 1995). This investigations showed that the capacity to inducesuch negative super coils was in all derivatives higher than in theunmodified recombinant HMGI-C protein used as a control. The allowableconclusion that, among others, the interaction of the proteins with theDNA affects the therapeutic efficacy, leads to the deduction that allsequences shown possess an increased efficacy with regard to theapplications mentioned.

Polypeptides Encoded by Polynucleotides Comprising the Sequences of SEQID NOs: 1-19 Promote DNA Bending

Translation products that include polypeptide sequences encoded by SEQID NOs: 1-19 as well as the native HMGI genes/MAG gene possess a DNArelaxing or DNA bending activity which is exercised upon binding of thetranslation products to DNA sequences (see Example 11). Due to thischange in the bending angle of the DNA in the promoter region of variousgenes a first access of a transcription complex or an access of adifferent transcription complex to the promoter region is possible, thusallowing for the modulation of expression of some distinct genes, asdescribed below. Notably, the gene products of both the native sequencesof HMGI genes/MAG genes, as well as the translation products of theaberrant transcripts according to SEQ ID NOs: 1-19 include at leastexons 1-3, wherein each of the exons encodes a DNA binding domain. Eachof said domains is able to bind to an AT “hook” (an AT-rich DNAsequence) which is present in the promoter region of the gene to beactivated. Typically, it is sufficient that two of the domains bind tosaid AT hooks and this interaction provides for the bending of the DNAstructure in the promoter region with the above-specified consequencesof facilitating the formation of a transcription complex.

Polypeptides Including Sequences Encoded by the HMGI Genes/MAG Genes andSEQ ID NOs: 1-19 Affect the Regulation of Genes that InfluenceDevelopment of Mesenchymal Tissues

The above-specified characteristics of the HMGI genes/-MAG genes and SEQID NOs: 1-19, namely to exhibit three AT hook binding domains, makes thegene products of the aforementioned nucleic acid sequences suitable formodulating the expression of genes that possess AT-rich DNA sequences(AT hooks), preferably in a promoter region.

Furthermore it is now know that the DNA relaxing/bending activity oftranslation products of HMGI genes/MAG genes/SEQ ID NOs: 1-19 acts onproliferatively active genes in the embryogenic phase (see Examples 8,1), particularly genes for the development of mesenchymal tissues.

Products of the HMGI Genes/MAG Genes and SEQ ID NOs: 1-19 are Useful forTreating Tumors, Promoting Angiogenesis, Treating Endometriosis,Stimulating Tissue Development and Contraception (1) Treatment of Tumors

(a) Benign Tumors

-   -   It has now been discovered that a mutation in the HMGI gene, or        in close proximity thereto, is sufficient to induce a benign        tumor (see Example 2). More particularly, it has been found that        in benign tumors the chromosomal breakpoints can be both within        the sequence of the HMGI genes/MAG genes or outside thereof. In        the first case the conclusion can be drawn that translation        products of aberrant transcripts, such as those disclosed in SEQ        ID NOs: 1-19, are responsible for the observed tumors (see        Example 2). In the second case, i.e., the chromosomal breakpoint        is outside said genes, it is suggested that even wild type        translation products, i.e., native HMGI genes/MAG genes, can        also be responsible for the observed tumor. In the latter case        it is noteworthy that changes in both the upstream and more        particularly in the downstream environment of the native nucleic        acid sequences are responsible for the observed HMGI genes/MAG        gene expression which cannot be observed under normal conditions        in tumor-free tissue.

(b) Malignant Tumors

-   -   It has been discovered that increased levels of translation        products encoded by HMGI genes/MAG genes and SEQ ID NOs: 1-19        correlate with unfavorable tumor prognosis. Accordingly,        detecting increased levels of these translation products        compared with non-tumor or tumor tissue, is useful for        determining the prognosis of a tumor. The tumor prognosis        correlated inversely with the levels of these translation        products.    -   The conclusion that gene products, or more particularly        translation products of HMGI genes/MAG genes/SEQ ID NOs: 1-19,        are useful for tumor therapy was based on the finding that tumor        progression and expression of HMGI genes/MAG genes/SEQ ID NOs:        1-19 correlated with an unfavorable prognosis of the tumor.        Accordingly, inhibiting tumor progression by reducing        transcriptional activity of the HMGI genes/MAG genes/SEQ ID NOs:        1-19 would inhibit tumor progression, thereby leading to        improved prognosis of malignant tumors.

(2) Angiogenesis

-   -   It was unexpectedly discovered that benign tumors contain blood        vessels derived from the tumor itself (see Example 5) whereas        blood vessels normally grow from the outside of the tumor into        the same. Under the influence of HMGI/MAG gene translation        products, and those of SEQ ID NOs: 1-19, new vessels can be        generated within the tumor itself. Accordingly, HMGI genes/MAG        genes/SEQ ID NOs: 1-19, and particularly their translation        products are suitable for promoting angiogenesis in vivo.

(3) Endometriosis

-   -   It was discovered that endometriosis afflicted tissue in which        HMGI, particularly HMGI-Y, was expressed (see Example 6). This        was in contrast to the normal expression pattern of the lining        of the corpus uteri. Based on this finding, it was considered        that endometriosis might be a condition similar to the condition        of endometrial polyps and to tumors observed in other tissues        and organs with regard to the fact that HMGI-expression was        increased. Tissue afflicted in the case of endometriosis was        characterized in that both mesenchymal and epithelial tissues        showed increased proliferation. Accordingly, treatments that        reduced expression of HMGI genes/MAG genes/SEQ ID NOs: 1-19,        more preferably HMGI-Y expression, in the lining of the corpus        uteri would improve symptoms associated with endometriosis.

(4) Tissue Regeneration

-   -   While studying the expression of HMGI genes/MAG genes and        polynucleotides having the sequences of SEQ ID NOs: 1-19 in        benign tumors it was discovered that tissue could regenerate        under the influence of the HMGI mutations, which lead either to        the formation of wild type translation products of the HMGI/MAG        genes or aberrant proteins (such as those encoded by SEQ ID NOs:        1-19) (see Examples 4, 9). Tissue regenerated under these        conditions was identical to the tissue from which the tumor        originated. This was observed for fatty or adipose tissue,        cartilage, more particularly hyaline cartilage and smooth        muscle. In all of these cases the regenerated tissue exhibited        all the characteristics of the differentiated tissue from which        it originated and was thus not dedifferentiated, as would have        been expected based on knowledge about other tumors that        typically exhibit tumor-derived cells showing distinct        dedifferentiation.

Regenerated fatty tissue may be used in applications that includeplastic surgery. Regeneration of cartilage will be useful for repair ofboth traumatic injury and degenerative changes, including sports damagesand arthrosis.

(5) Contraception

-   -   It now has been discovered that formation of the placenta        requires activity of the HMGI genes (see Example 7). It has        further been shown that if HMGI-C is inactive this lack can be        compensated by expression of HMGI-Y. Accordingly, it is thus        concluded that contraception can be performed by blocking        translation and/or transcription of the HMGI/MAG genes.

Methods Based on Modulating the Expression of HMGI Genes/MAG Genes andDerivatives Thereof

Methods useful in connection with: (1) the treatment of tumors; (2)treatment of endometriosis; and (3) contraception, involve blocking orinhibiting the activity of the translation products of the HMGIgenes/MAG genes and their derivatives, including SEQ ID NOs: 1-19. Thiscan be accomplished by inhibiting mRNA translation or transcriptionalactivation using antisense nucleic acids. Alternatively, ribozymestargeted to the mRNAs encoding these proteins can be made and used toinactivate the mRNAs. Still another method of blocking or inhibiting theactivity of the translation products of the HMGI genes/MAG genes andtheir derivatives, including SEQ ID NOs: 1-19 includes producing highintracellular levels of translation products or mimics thereof. Morespecifically, high intracellular levels of translation products of theHMGI genes/MAG genes or the sequences of SEQ ID NOs: 1-19 can be usedfor competitive binding to target sequences so that the promoternormally activated by the translation products of the HMGI genes/MAGgenes/SEQ ID NOs: 1-19 can no longer be activated (“flooding” of thecell). Molecules which mimic targets of the translation products of theHMGI genes/MAG genes/SEQ ID NOs: 1-19 can compete with their naturaltargets, thereby resulting in inhibition of the intracellularly presenttranslation products of the HMGI genes/MAG genes/SEQ ID NOs: 1-19. Suchmolecules can be selected from the group that includes nucleic acidsequences comprising at least one AT hook or at least one AT hook-likestructure, and molecules exhibiting the structure and/or bindingcharacteristics of AT hooks. Preferably, the molecule is a nucleic acidmolecule, however, it is not restricted to polynucleotides.

Methods useful for promoting tissue regeneration involve stimulating theexpression of HMGI genes/MAG genes or their derivatives, including SEQID NOs: 1-19. For example, this activation can be accomplished byadministering cells in vitro or in vivo a chemical compound. Such acompound may act either specifically or non-specifically. Activation ofHMGI genes/MAG genes/SEQ ID NOs: 1-19 can be promoted, for example, bycontacting cells with different compounds, including phorbol esters. Isalso is possible to activate genes responsible for further growth ofdifferentiated tissue by introducing HMGI genes/MAG genes including SEQID NOs: 1-19 into the respective cells and tissue by means of genetherapy. For this purpose the respective nucleic acid sequences,particularly according to SEQ ID NOs: 1-19, are put under control of astrong promoter, which optionally can be activated and deactivated uponadministration of a stimulus to the cell/tissue. Yet another approachfor promoting tissue regeneration involves administering directly to therespective cell/tissue a translation product, either a peptide or aprotein, that is derived from HMGI genes/MAG genes or SEQ ID NOs: 1-19.Due to the low molecular weight of any of the aforementioned translationproducts these peptides/proteins can easily be applied to the cell, forexample using encapsulation delivery systems.

Methods useful for treating angiogenesis vary according to whether it isintended to increase or decrease angiogenesis in a particular situation.In the case where growth of vessels is to be promoted, such as in caseof improving vessel supply of infarct-damaged myocardial tissue, anincreased expression of HMGI genes/MAG genes including SEQ ID NOs: 1-19is to be realized which can be performed according to the measures asoutlined above. However, if angiogenesis is to be inhibited, such asmight be the case in the treatment of tumor diseases or diseases of theeye resulting from neovascularization, expression of the HMGI genes/MAGgenes, including SEQ ID NOs: 1-19, is to be suppressed according to oneof the above-specified approaches.

The features of the invention revealed in the preceding description andin the claims can, both alone and in any combination, be of significancefor the realization of the invention in its various forms ofimplementation.

1. A method for regenerating tissue, comprising administering to saidtissue a translation product of a nucleic acid sequence wherein saidnucleic acid sequence is an HMGI gene.
 2. A method according to claim 1,wherein tissue regeneration is performed in situ.
 3. A method accordingto claim 2, wherein a mesenchymal tissue is selected from the groupconsisting of cartilage tissue, muscle tissue, fatty or adipose tissue,connective tissue and supporting tissue.
 4. A method according to claim1, wherein said translation product is administered via an encapsulationtechnique to said tissue.
 5. A method according to claim 1, whereintissue is regenerated by the steps comprising: carrying out theadministering step to at least one cell to provide at least oneadministered cell; co-culturing said at least one administered cell withcells of said tissue in vitro; and propagating said co-cultured cells toobtain regenerated tissue.
 6. A method according claim 1, wherein thetissue to be regenerated is mesenchymal tissue.
 7. A method according toclaim 6, wherein the mesenchymal tissue is selected from the groupconsisting of cartilage tissue, muscle tissue, fatty or adipose tissue,connective tissue and supporting tissue.
 8. The method of claim 5,wherein the administered cell and the cells of said tissue are from thesame tissue.
 9. The method of claim 5, wherein the administered cell isa tumor cell.
 10. The method of claim 9, wherein the regenerated tissueis cartilage tissue.
 11. The method of claim 5, wherein the tissue is amesenchymal tissue which is selected from the group consisting ofcartilage tissue, muscle tissue, fatty or adipose tissue, connectivetissue and supporting tissue.